Fluorenone derivatives, process for preparing the same and central or peripheral nerve degeneration repair and protective agent

ABSTRACT

The present invention provides a novel fluorenone derivatives represented by the formula: ##STR1## wherein R a  -R g  are defined in the specification, and a method for repairing and protecting central or peripheral nerve degeneration comprising use of a fluorenone derivative represented by the formula: ##STR2## wherein R 1 , R 2  p and q are as defined in the specification as an active component.

TECHNICAL FIELD

The present invention relates to a fluorenone derivative, a process forpreparing the same and a central or peripheral nerve degeneration repairor protective agent.

BACKGROUND ART

At present, it is suggested that senile demantia represented byAlzheimer's disease causes serious change in central cholinergic nervoussystem, which results in deterioration of function thereof Perry, E. K.and Perry, R. H. "Biochemistry of Dementia", page 135 (1980), John Wiley& Sons.,!.

Accordingly, a compound having repair capacity (e.g. survival effect andneulite stretching effect) and protective action of nerve cells can beeffectively used as a remedy or a preventive for senile demantiarepresented by Alzheimer's disease, Down's syndrome, Huntington'schorea, intellectual/learning disturbance (e.g. amnesia, memorydisorder, etc.), and aftereffect and neuropathy caused by deteriorationof acetylcholinergic nervous system function due to head injury,cerebral operation, drug intoxication, circulatory disorder, cerebralmetabolic disorder, encephalitis, etc. J. W. Geddes et al., Science,230, 1179-1181 (1985)!.

Heretofore, NGF (nerve growth factor), GM1 (ganglioside) and the likehave merely been known as the compound having repair capacity for nervecells degeneration as described above. NGF is described, for example, inNeuroscience Hefti, F. et al., 14, 55-68 (1985)!, Journal ofNeuroscience Frantz Hefti, 6, 2155-2162 (1986)!, Proc. Natl. Acad. Sci.USA, L. R. Williams et al., 83, 9231-9235 (1986)!, Science L. E. Kromer,235, 214-216 (1986)! and the like. In addition, GM1 is described, forexample, in Science Fred J. Roisen et al., 214, 577-578 (1981)!, BrainRes. M. V. Sofroniew et al. 398, 393-396 (1986)!, Brain Res. M.Gradkowska et al., 375, 417-422 (1986)! and the like.

DISCLOSURE OF INVENTION

A fluorenone derivative of the present invention is represented by thefollowing formulas (A) to (D). ##STR3## wherein R^(a) is a hydrogenatom, a lower alkenyl group or an acetyl group;

R^(b) and R^(c) are the same or different and are a hydrogen atom, alower alkenyl group, a lower alkyl group, a halogen atom, a lower alkoxygroup, a lower alkylthio group, a lower alkenyloxy group, a group of theformula: ##STR4## (wherein R⁸ and R⁹ are the same or different andindicate a hydrogen atom, a lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a pyrimidinyl group orpyrazinyl group, and R⁸ and R⁹ may bond together with the nitrogen atomto which they are attached to form a 5- or 6-membered saturatedheterocycle through a nitrogen or oxygen atom or not (i.e., having anitrogen or oxygen atom or not as other hetero atom), the heterocycleoptionally containing a substituent selected from the group consistingof a lower alkyl group and a lower alkoxycarbonyl group; and A is alower alkylene group), an imidazolyl-substituted lower alkyl group, alower alkoxy-substituted lower alkyl group, a hydroxyl group-substitutedlower alkoxy-lower alkoxy-substituted lower alkyl group or a lowertrialkyl-substituted ammonium-substituted lower alkyl group;

R^(d), R^(e), R^(f) and R^(g) are the same or different and are; ahydrogen atom, a lower alkenyl group, a lower alkyl group, a halogenatom, a lower alkoxy group, a lower alkenyloxy group, a group of theformula: ##STR5## (wherein R⁸ and R⁹ are as defined above), animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a pyridylthio-substituted lower alkyl group, aphenylthio-substituted lower alkyl group optionally containing a loweralkoxy group as a substituent on a phenyl ring, abenzimidazolylthio-substituted lower alkyl group, animidazolylthio-substituted lower alkyl group, a lower alkanoyl group, acycloalkylthio-substituted lower alkyl group, a cyano-substituted loweralkyl group or a lower trialkyl-substituted ammonium-substituted loweralkyl group;

(1) R^(c) and R^(g) must not be methyl groups when R^(a), R^(b), R^(d),R^(e) and R^(f) are hydrogen atoms,

(2) R^(f) must not be a methyl group when R^(a), R^(b), R^(c), R^(d),R^(e) and R^(g) are hydrogen atoms,

(3) R^(g) must not be a methyl group when R^(b), R^(c), R^(e) and R^(f)are hydrogen atoms, and R^(a) is a hydrogen atom or an acetyl group,

(4) R^(b) and R^(f) must not be methyl groups when R^(a), R^(c), R^(d),R^(d), R^(e) and R^(g) are hydrogen atoms,

(5) R^(b) must not be an allyl group when R^(c), R^(d), R^(e), R^(f) andR^(g) are hydrogen atoms, and R^(a) is a hydrogen atom or an acetylgroup,

(6) any one to three of R^(b) to R^(g) must not be lower alkyl groups orhalogen atoms when R^(a) is a hydrogen atom,

(7) R^(a) must not be a hydrogen atom and an acetyl group when R^(b),R^(c), R^(d), R^(e), R^(f) and R^(g) are hydrogen atoms,

(8) R^(f) must not be a cyano-substituted lower alkyl group when R^(a),R^(b), R^(c), R^(d), R^(e) and R^(g) are hydrogen atoms, and

(9) any one of R^(d), R^(e), R^(f) and R^(g) must not be a hydrogen atomwhen R^(b) and R^(c) are hydrogen atoms and any one of R^(d), R^(e),R^(f) and R^(g) is a lower alkenyl group!; ##STR6## wherein R^(a) is asdefined above; q is an integer of 1 to 4; r is an integer of 1 to 3;

R^(1a) has the same meanings as R^(b) and R^(c) defined above;

R^(2a) has the same meanings as R^(d) to R^(c) defined above; providedthat,

(1) R^(1a) must not be a hydrogen atom when R^(a) is a hydrogen atom oran acetyl group and R^(2a) is a lower alkoxy group,

(2) R^(2a) must not be a lower alkenyl group when R^(1a) is a hydrogenatom and q is 1, and

(3) a total of r and q must not be an integer of 2 to 4 when R^(a) is ahydrogen atom and R^(1a) and R^(2a) indicate a hydrogen atom, a halogenatom or a lower alkyl group!; ##STR7## wherein R^(1a), R^(2a), R^(a) andr are as defined above; R^(h) is a hydrogen atom, a lower alkenyl groupor an acetyl group; s is an integer of 1 to 3; provided that,

(1) any one of R^(a) and R^(h) is an acetyl group when R^(1a) and R^(2a)are hydrogen atoms, and

(2) a 4-position of a fluorenone skeleton must not be substituted withR^(1a) when R^(a) and R^(h) are hydrogen atoms or acetyl groups andR^(2a) is a hydrogen atom, r is 1 and R^(1a) is a methoxy group!; and##STR8## wherein R^(1a), R^(2a), R^(a), R^(h), r and s are as definedabove; provided that,

(1) both R^(1a) and R^(2a) must not be hydrogen atoms when R^(a) andR^(h) are hydrogen atoms or acetyl groups,

(2) 1- and 8-positions of a fluorenone skeleton must not be substitutedwith R^(1a) and R^(2a) when R^(a) and R^(h) are hydrogen atoms, r and sare 1 and R^(1a) and R^(2a) are methyl groups, and

(3) 3- and 6-positions of a fluorenone skeleton must not be substitutedwith R^(1a) and R^(2a) when R^(a) and R^(h) are hydrogen atoms, r and sare 1 and R^(1a) and R^(2a) are halogen atoms!.

The central and/or peripheral nerve cells degeneration repair orprotective agent of the present invention contains a fluorenonederivative represented by the formula: ##STR9## wherein R¹ is a hydrogenatom, a hydroxyl group, a lower alkenyl group, a lower alkyl group, ahalogen atom, a lower alkoxy group, a lower alkylthio group, a loweralkanoyloxy group, a lower alkenyloxy group, a group of the formula:##STR10## (wherein R⁸ and R⁹ are as defined above), animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a hydroxyl group-substituted lower alkoxy-loweralkoxy-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group;

R² is a hydrogen atom, a hydroxyl group, a lower alkenyl group, a loweralkyl group, a halogen atom, a lower alkoxy group, a lower alkanoyloxygroup, a lower alkenyloxy group, a group of the formula: ##STR11##(wherein R⁸, R⁹ and A are as defined above), an imidazolyl-substitutedlower alkyl group, a lower alkoxy-substituted lower alkyl group, apyridylthio-substituted lower alkyl group, a phenylthiothio-substitutedlower alkyl group optionally containing a lower alkoxy group as asubstituent on a phenyl ring, a benzimidazolylthio-substituted loweralkyl group, an imidazolylthio-substituted lower alkyl group, a loweralkanoyl group, a cycloalkylthio-substituted lower alkyl group, acyano-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group;

p and q indicate an integer of 1 to 4; and

R¹ and R² may be the same or different! as an active component.

The fluorenone derivative represented by the above formula (1) has anaction of extremely accelerating survival of nerve cells and stretchingof neulite and further increasing enzyme activity of cholineacetyltransferase (CHAT) as an acetylcholine synthesis enzyme ofcolinergic nerve cells. Accordingly, the compound represented by theabove formula (1) has particularly an action of accelerating survivaland growth of colinergic nerve cells of a central nervous system and aprotective action against the disorder thereof.

Further, the fluorenone derivative represented by the above formula (1)has a peripheral nerve degeneration repair or protective action and isuseful as a peripheral nerve degeneration repair or protective agent.For example, it is useful as an effective remedy for neuropathy due toinjury, neuropathy due to metabolic factor such as diabetic neuropathy,neuropathy caused by side effect of poison or drug, peripheralneuropathy such as multiple neuritis and the like.

An enzyme is essential to life-sustaining of a living body, e.g. energyproduction, metabolism, etc. The enzyme becomes a so-called activeenzyme such as oxygen anion radical, peroxidized ion, hydroxy radical,etc. by the reaction in energy production system, enzyme reaction,reaction due to ultraviolet rays, radiation, etc. The active oxygenspecies are useful for the living body in view of bactericidal action ofoxygenase, white blood cells and the like. On the other hand, theyaccelerate hyperoxidation of an unsaturated fatty acid formingphospholipid of biomembrane, such as oleic acid, linolic acid, linolenicacid, arachidonic acid, etc. to form lipoperoxide. The resultinglipoperoxide cause formation of alkoxy radical and hydroxy radical,similar to the above active oxygen species to attach the biomembrane,which results in membrane disorder and devitalization of various usefulenzymes see Metabosilm 15 (10), 1978, special issue of "Active Oxygen"!.

In the living body, for example, enzymes having something to do withmetabolic devitalization of the above active oxygen species, such assuperoxide dismutase (SOD), catalase, glutathione peroxidase, etc. arepresent, and vitamins having various antioxidation capacities are alsopresent, in addition to α-tocopherol (vitamin E). According to theaction of these enzymes and vitamins, normal life-sustaining can beconducted. However, failure is arisen in a suitable defensive mechanismdue to the above enzymes and vitamins for some reason, or formation ofthe active oxygen species which surpass a capacity of the defensivemechanism or formation/accumulation of lipoperoxide is sometimesrecognized. When such a failure is arisen in the defensive mechanism,serious disorders such as various diseases due to platelet aggregation,inflammation, hepatopathy, arterial sclerosis, cythemolysis, aging orsenile dementia, retinopaty, pulmonary disturbance, cardiac/pulmonarydisturbance due to certain drug, ischemic angiopathy and the like arearisen with the chain reactive progress of the hyperoxidation reaction.

A compound having an action of scavenging active oxygen species(radical) which have hitherto been considered to be a main factor of theabove various disorders and preventing or reducingformation/accumulation of lipoperoxide in the living body is normallyreferred to as an antioxidant. Actually, several examples of thepreventive and therapeutic effect thereof on the above various diseaseshave been reported. As the reported antioxidant, for example, there areenzyme including the above SOD Superoxide and Medical, YoshihikoOyanagi, 1981, Kyoritsu Shuppansha, pages 137-141!, butylatedhydroxytoluene (BHT), butylated hydroxyanisol (BHA), α-tocopherol(vitamin E) Makoto Mino and Hidetaka Tanaka, Medicinal Journal, 19 (12),1983, pages 2351-2359; and Toshihiko Suematsu, Medicinal Journal, 19(5), 1983, pages 909-914! and the like.

The fluorenone derivative represented by the above formula (1)(hereinafter referred to as a "compound of the present invention") hasan action of scavenging active oxygen species and preventing/reducingformation of lipoperoxide in the living body. Accordingly, the compoundof the present invention is useful as a preventive or a remedy forvarious disorders/diseases caused by the overformation of the aboveactive oxygen species, accumulation of lipoperoxide in the living bodyor failure of the defensive mechanism against them. For example, it isalso useful as medicines such as antiarteriosclerotic agent,carcinogenesis preventive, anti-inflammatory agent, analgesic,autoimmune disease remedy, platelet aggregation inhibitor, hypotensivedrug, antilipemic agent, preventive and remedy for prematurityretinopathy and cataract and the like. Further, the compound of thepresent invention is not only useful as the above medicines, but alsouseful as antioxidants for fats and oils contained in processed foods.

Further, the compound of the present invention has a cyclic guanosine3', 5'-monophosphate-phosphodiesterase (c-GMP-PDE) inhibition action,and also has an antiplatelet action, antineutrophil action,antivasospasm action, angiectasia action and effect-enhancing action ofEDRF (endothelium-derived relaxing factor) and nitro-based vasodialtorby increasing c-GMP concentration.

Accordingly, the compound of the present invention is useful fortreating and preventing diseases such as stable/unstable type anginapectoris, hypertension, tenal hypertension, congestive heart failure,arterial sclerosis, peripheral angiopathy, e.g. post PTCA(post-percutaneous transluminal coronary angioplastry), cerebralhemorrhage, bronchitis, chronic asthma, allergic asthma, allergicrhinitis, glaucoma and the like.

Examples of the respective groups defined in the present specificationare as follows.

Examples of the lower alkyl group include straight- or branched-chainalkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, pentyl, hexyl groups and the like.

Examples of the lower alkenyl group include straight- or branched-chainalkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl,2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl groups andthe like.

Examples of the halogen atom include fluorine, chlorine, bromine andiodine atoms and the like.

Examples of the lower alkoxy group include straight- or branched-chainalkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy groups andthe like.

Examples of the lower alkylthio group include straight- orbranched-chain alkylthio groups having 1 to 6 carbon atoms such asmethylthio, ethylthio, propylthio, isopropylthio, butylthio,tert-butylthio, pentylthio, hexylthio groups and the like.

Examples of the lower alkanoyloxy group include straight- orbranched-chain alkanoyloxy groups having 1 to 6 carbon atoms such asformyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,pentanoyloxy, tert-butylcarbonyloxy, hexanoyloxy groups and the like.

Examples of the lower alkenyloxy group include straight- orbranched-chain alkenyloxy groups having 2 to 6 carbon atoms such asvinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 1-methylallyloxy,2-pentenyloxy, 2-hexenyloxy groups and the like.

Examples of the lower alkoxycarbonyl-substituted lower alkyl groupinclude straight- or branched-chain alkoxycarbonylalkyl groups having 1to 6 carbon atoms in each of which alkoxycarbonyl moiety is a straight-or branched-chain alkoxycarbonyl group having 1 to 6 carbon atoms, suchas methyoxycarbonylmethyl, 3-methoxycarbonylpropyl,ethoxycarbonylmethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl,5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl,1,1-dimethyl-2-butoxycarbonylethyl,2-methyl-3-tert-butoxycarbonylpropyl, 1-methoxycarbonylisopentyl,2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl groups and the like.

Examples of the lower alkoxycarbonyl group include straight- orbranched-chain alkoxycarbonyl groups having 1 to 6 carbon atoms such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonylgroups and the like.

Examples of the 5- or 6-membered saturated heterocycle formed by bondingR⁸ and R⁹ together with the nitrogen atom to which they are attachedthrough a nitrogen or oxygen atom or not include pyrrolidinyl,piperidinyl, piperazinyl, morpholino groups and the like.

Examples of the heterocycle group substituted with a substituentselected from the group consisting of a lower alkyl group and a loweralkoxycarbonyl group include the heterocycle groups substituted with 1to 3 susbtituents selected from the group consisting of a straight- orbranched-chain alkyl group having 1 to 6 carbon atoms and a straight- orbranched-chain alkoxycarbonyl group having 1 to 6 carbon atoms, such as4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl,2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl,3-pentylmorpholino, 4-hexylpiperazinyl, 4-ethoxycarbonylpiperazinyl,3-methoxycarbonylmorpholino, 3-methyl-4-ethoxycarbonylpiperidinyl,2-methoxycarbonylpyrrolidinyl, 3-ethoxycarbonylpyrrolidinyl groups andthe like.

Examples of the imidazolyl-substituted lower alkyl group includeimidazolyl-substituted alkyl groups in each of which alkyl moiety is astraight- or branched-chain alkyl group having 1 to 6 carbon atoms, suchas (1-imidazolyl)methyl, 2-(1-imidazolyl)ethyl, 1-(2-imidazolyl)ethyl,3-(4-imidazolyl)propyl, 4-(5-imidazolyl)butyl, 5-(1-imidazolyl)pentyl,6-(2-imidazolyl)hexyl, 1,1-dimethyl-2-(1-imidazolyl)ethyl,2-methyl-3-(1-imidazolyl)propyl groups and the like.

Examples of the lower alkoxy-lower alkyl group include straight- orbranched-chain alkoxyalkyl groups having 1 to 6 carbon atoms in each ofwhich alkyl moiety is a straight- or branched-chain alkyl group having 1to 6 carbon atoms, such as methoxymethyl, 2-ethoxymethyl,1-methoxymethyl, 3-methoxypropyl, 4-ethoxybutyl, 6-propoxyhexyl,5-isopropoxypentyl, 1,1-dimethyl-2-butoxyethyl,2-methyl-3-tert-butoxypropyl, 2-pentyloxyethyl, hexyloxymethyl groupsand the like.

Examples of the lower alkylene group include straight- or branched-chainalkylene groups having 1 to 6 carbon atoms such as methylene, ethylene,trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene,1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene,pentamethylene, hexamethylene groups and the like.

Examples of the pyridylthio-substituted lower alkyl group includepyridylthio-substituted alkyl groups in each of which alkyl moiety is astraight- or branched-chain alkyl group having 1 to 6 carbon atoms, suchas (2-pyridyl)thiomethyl, (3-pyridyl)thiomethyl, (4-pyridyl)thiomethyl,2-(2-pyridyl)thioethyl, 2-(3-pyridyl)thioethyl, 2-(4-pyridyl)thioethyl,3-(2-pyridyl)thiopropyl, 3-(3-pyridyl)thiopropyl,3-(4-pyridyl)thiopropyl, 4-(2-pyridyl)thiobutyl, 4-(3-pyridyl)thiobutyl,4-(4-pyridyl)thiobutyl, 5-(2-pyridyl)thiopentyl,5-(3-pyridyl)thiopentyl, 5-(4-pyridyl)thiopentyl,6-(2-pyridyl)thiohexyl, 6-(3-pyridyl)thiohexyl, 6-(4-pyridyl)thiohexyl,1,1-dimethyl-2-(2-pyridyl)thioethyl,1,1-dimethyl-2-(3-pyridyl)thioethyl, 1,1-dimethyl-(4-pyridyl)thioethyl,2-methyl-3-(2-pyridyl)thiopropyl, 2-methyl-3-(3-pyridyl)thiopropyl,2-methyl-3-(4-pyridyl)thiopropyl groups and the like.

Examples of the phenylthio-lower alkyl group optionally containing alower alkoxy group as a substituent on a phenyl ring include phenylthioalkyl groups in each of which alkyl moiety optionally containing 1 to 3straight- or branched-chain alkoxy groups having 1 to 6 carbon atoms asa substituent on a phenyl ring is a straight- or branched chain alkylgroup having 1 to 6 carbon atoms, such as phenylthiomethyl,1-phenylthioethyl, 2-phenylthioethyl, 1-phenylthioethyl,3-phenylthiopropyl, 4-phenylthiobutyl, 5-phenylthiopentyl,6-phenylthiohexyl, 1,1-dimethyl-2-phenylthioethyl,2-methyl-3-phenylthiopropyl, (2-methoxyphenyl)thiomethyl,(3-methoxyphenyl)thiomethyl, (4-methoxyphenyl)thiomethyl,2-(4-methoxyphenyl)thioethyl, 1-(2-ethoxyphenyl)thioethyl,3-(4-isopropoxyphenyl)thiopropyl, 4-(3-pentyloxyphenyl)thiobutyl,5-(4-hexyloxyphenyl)thiopentyl, 6-(2-butyloxyphenyl)thiohexyl,(3,4-dimethoxyphenyl)thiomethyl, (3-ethoxy-4-methoxyphenyl)thiomethyl,(2,3-dimethoxyphenyl)thiomethyl, (2,6-dimethoxyphenyl)thiomethyl,(3,4,5-trimethoxyphenyl)thiomethyl groups and the like.

Examples of the benzimidazolylthio-substituted lower alkyl group includebenzimidazolylthio-substituted straight- or branched chain alkyl groupshaving 1 to 6 carbon atoms such as (benzimidazole-2-yl)thiomethyl,1-(benzimidazole-4-yl)thioethyl, 2-(benzimidazole-5-yl)thioethyl,3-(benzimidazole-6-yl)thiopropyl, 4-(benzimidazole-2- yl)thiobutyl,5-(benzimidazole-7-yl)thiopentyl, 6-(benzimidazole-2-yl)thiohexyl,1,1-dimethyl-2-(benzimidazole-2-yl)thioethyl,2-methyl-3-(benzimidazole-2-yl)thiopropyl groups and the like.

Examples of the imidazolylthio-substituted lower alkyl group includeimidazolylthio-substituted alkyl groups in each of which alkyl moiety isa straight- or branched-chain alkyl group having 1 to 6 carbon atoms,such as (2-imidazolyl)thiomethyl, 2-(2-imidazolyl)thioethyl,1-(2-imidazolyl)thioethyl, 3-(4-imidazolyl)thiopropyl,4-(5-imidazolyl)thiobutyl, 5-(4-imidazolyl)thiopentyl,6-(2-imidazolyl)thiohexyl, 1,1-dimethyl-2-(2-imidazolyl)thiohexyl,1,1-dimethyl-2-(2-imidazolyl)thioethyl,2-methyl-3-(5-imidazolyl)thiopropyl groups and the like.

Examples of the lower alkanoyl group include straight- or branched chainalkanoyl group having 1 to 6 carbon atoms such as formyl, acetyl,propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoylgroups and the like.

Examples of the cycloalkylthio-substituted lower alkyl group includecycloalkylthioalkyl groups having 3 to 8 carbon atoms in each of whichalkyl moiety is a straight- or branched-chain alkyl group having 1 to 6carbon atoms, such as cyclopropylthioethyl, 2-cyclobutylthioethyl,1-cyclopentylthioethyl, 3-cyclohexylthiopropyl, cyclohexylthiomethyl,4-cycloheptylthiobutyl, 5-cyclooctylthiopentyl, 6-cyclohexylthiohexyl,1,1-dimethyl-2-cyclohexylthioethyl, 2-methyl-3-cyclohexylthiopropylgroups and the like.

Examples of the cyano-substituted lower alkyl group include cyanoalkylgroups in each of which alkyl moiety is a straight- or branched-chainalkyl group having 1 to 6 carbon atoms, such as cyanomethyl,2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl,6-cyanohexyl, 1,1-dimethyl-2-cyanoethyl, 2-methyl-3-cyanopropyl groupsand the like.

Examples of the hydroxyl group-substituted lower alkoxy-loweralkoxy-substituted lower alkyl group include straight- or branched-chainalkoxy group having 1 to 6 carbon atoms (containing 1 to 3 hydroxylgroups)-substituted straight- or branched chain alkoxy group having 1 to6 carbon atoms-substituted straight- or branched-chain alkyl groupshaving 1 to 6 carbon atoms, such as 2- 2-(2-hydroxyethoxy)ethoxy!propyl,hydroxymethoxymethoxymethyl, 2- 3-(2-hydroxyethoxy)propoxy!ethyl,(3,4,5-trihydroxypentyloxy)methoxy!methyl, 1-4-(1-hydroxyethoxy)butoxy!ethyl, 3- 6-(3-hydroxypropoxy)hexyloxy!propyl,4- 5-(2,3-dihydroxypropoxy)pentyloxy!butyl, 5-1,1-dimethyl-2-(4-hydroxybutoxy)ethoxy!pentyl, 6-2-methyl-3-(3,4-dihydroxybutoxy)propoxy!hexyl,2-(1,1-dimethyl-2-hydroxyethoxy)ethoxy!methyl, 2-(5-hydroxypentyloxy)methoxy!ethyl, 3-(6-hydroxyhexyloxymethoxy)propyl,(2-methyl-3-hydroxypropoxy)methoxy!methyl groups and the like.

Examples of the lower trialkyl-substituted ammonium-substituted loweralkyl group include ammonium alkyl groups in each of which lower alkylmoiety having 3 straight- or branched chain alkyl groups having 1 to 6carbon atoms is a straight- or branched-chain alkyl group having 1 to 6carbon atoms, such as trimethylammoniummethyl,2-(triethylammonium)ethyl, 1-(tripropylammonium)ethyl,3-(tributylammonium)propyl, 4-(tripentylammonium)butyl,5-(triethylammonium)pentyl, 6-(trihexylammonium)hexyl,1,1-dimethyl-2-(N-methyl-N-ethyl-N-propylammonium)ethyl,2-methyl-3-(N,N-dimethyl-N-ethylammonium)propyl,3-(N-propyl-N,N-dimethylammonium)propyl,4-(N,N-dihexyl-N-methylammonium)butyl,5-(N-pentyl-N-methyl-N-ethylammonium)pentyl,6-(N-butyl-N-methyl-N-ethylammonium)hexyl groups and the like.

The following compounds of various embodiments are included in thefluorenone derivative of the formula (1) as an active component of thecentral or peripheral nerve degeneration repair or protective agent ofthe present invention.

(1) A fluorenone derivative wherein R¹ is a hydroxyl group, a loweralkenyl group, a lower alkyl group, a halogen atom, a lower alkylthiogroup, a group of the formula: ##STR12## (wherein A, R⁸ and R⁹ are thesame as those defined in the above formula (A)), animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a hydroxyl group-substituted lower alkoxy-loweralkoxy-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group; R² is a hydroxyl group, a loweralkenyl group, a lower alkyl group, a halogen atom, a group of theformula: ##STR13## (wherein A, R⁸ and R⁹ are the same as those definedin the above formula (A)), an imidazolyl-substituted lower alkyl group,a lower alkoxy-substituted lower alkyl group, a pyridylthio-substitutedlower alkyl group, a phenylthio-substituted lower alkyl group optionallycontaining a lower alkoxy group as a substituent on a phenyl ring, abenzimidazolylthio-substituted lower alkyl group, animidazolylthio-substituted lower alkyl group, a lower alkanoyl group, acycloalkylthio-substituted lower alkyl group, a cyano-substituted loweralkyl group or a lower trialkyl-substituted ammonium-substituted loweralkyl group, or a salt thereof.

(2) A fluorenone derivative wherein R¹ is a hydrogen atom, a loweralkenyl group, a lower alkyl group, a halogen atom, a lower alkoxygroup, a lower alkylthio group, a lower alkanoyloxy group or a loweralkenyloxy group; and R² is the same as that defined in the above item(1), or a salt thereof.

(3) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (2); and R² is a hydrogen atom, a lower alkenyl group, alower alkyl group, a halogen atom, a lower alkoxy group, a loweralkanoyloxy group or a lower alkenyloxy group, or a salt thereof.

(4) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (1); and R² is the same as that defined in the above item(3), or salt thereof.

(5) A fluorenone derivative wherein R¹ is a lower alkenyl group, a loweralkyl group, a halogen atom, a lower alkoxy group, a lower alkylthiogroup, a lower alkanoyloxy group, a lower alkenyloxy group, a hydroxylgroup, a group of the formula: ##STR14## (wherein A, R⁸ and R⁹ are thesame as those defined in the above formula (A)), animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a hydroxyl group-substituted lower alkoxy-loweralkoxy-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group; R² is a lower alkenyl group, alower alkyl group, a halogen atom, a lower alkoxy group, a loweralkanoyloxy group, a lower alkenyloxy group, a hydroxyl group, a groupof the formula: ##STR15## (wherein A, R⁸ and R⁹ are the same as thosedefined in the above formula (A)), an imidazolyl-substituted lower alkylgroup, a lower alkoxy-substituted lower alkyl group, apyridylthio-substituted lower alkyl group, a phenylthio-substitutedlower alkyl group optionally containing a lower alkoxy group as asubstituent on a phenyl ring, a benzimidazolylthio-substituted loweralkyl group, an imidazolylthio-substituted lower alkyl group, a loweralkanoyl group, a cycloalkylthio-substituted lower alkyl group, acyano-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group, or a salt thereof.

(6) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (5); and R² is the same as that defined in the above item(1), or salt thereof.

(7) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (5); and R² is the same as that defined in the above item(3), or salt thereof.

(8) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (1); and R² is the same as that defined in the above item(5), or salt thereof.

(9) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (2); and R² is the same as that defined in the above item(5), or salt thereof.

(10) A fluorenone derivative wherein R¹ is a lower alkoxy group, a loweralkanoyloxy group or a lower alkenyloxy group; and R² is a lower alkoxygroup, a lower alkanoyloxy group or a lower alkenyloxy group, or a saltthereof.

(11) A fluorenone derivative wherein R¹ is a lower alkenyl group, alower alkyl group, a halogen atom or a lower alkylthio group; and R² isa lower alkenyl group, a lower alkyl group or a halogen atom, or a saltthereof.

(12) A fluorenone derivative wherein R¹ is a hydroxyl group, a group ofthe formula: ##STR16## (wherein A, R⁸ and R⁹ are the same as thosedefined in the above formula (A)), an imidazolyl-substituted lower alkylgroup, a lower alkoxy-substituted lower alkyl group, a hydroxylgroup-substituted lower alkoxy-lower alkoxy-substituted lower alkylgroup or a lower trialkyl-substituted ammonium-substituted lower alkylgroup; R² is a hydroxyl group, a group of the formula: ##STR17##(wherein A, R⁸ and R⁹ are the same as those defined in the above formula(A)), an imidazolyl-substituted lower alkyl group, a loweralkoxy-substituted lower alkyl group, a pyridylthio-substituted loweralkyl group, a phenylthio-substituted lower alkyl group optionallycontaining a lower alkoxy group as a substituent on a phenyl ring, abenzimidazolylthio-substituted lower alkyl group, animidazolylthio-substituted lower alkyl group, a lower alkanoyl group, acycloalkylthio-substituted lower alkyl group, a cyano-substituted loweralkyl group or a lower trialkyl-substituted ammonium-substituted loweralkyl group, or a salt thereof.

(13) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (10); and R² is the same as that defined in the aboveitem (1), or salt thereof.

(14) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (10); and R² is the same as that defined in the aboveitem (3), or salt thereof.

(15) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (10); and R² is the same as that defined in the aboveitem (5), or salt thereof.

(16) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (10); and R² is the same as that defined in the aboveitem (11) or salt thereof.

(17) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (10); and R² is the same as that defined in the aboveitem (12), or salt thereof.

(18) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (11); and R² is the same as that defined in the aboveitem (1), or salt thereof.

(19) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (11); and R² is the same as that defined in the aboveitem (3), or salt thereof.

(20) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (11); and R² is the same as that defined in the aboveitem (5), or salt thereof.

(21) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (11); and R² is the same as that defined in the aboveitem (10), or salt thereof.

(22) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (11); and R² is the same as that defined in the aboveitem (12), or salt thereof.

(23) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (12); and R² is the same as that defined in the aboveitem (1), or salt thereof.

(24) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (12); and R² is the same as that defined in the aboveitem (3), or salt thereof.

(25) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (12); and R² is the same as that defined in the aboveitem (5), or salt thereof.

(26) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (12); and R² is the same as that defined in the aboveitem (11), or salt thereof.

(27) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (12); and R² is the same as that defined in the aboveitem (10), or salt thereof.

(28) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (1); and R² is the same as that defined in the above item(10), or salt thereof.

(29) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (2); and R² is the same as that defined in the above item(10), or salt thereof.

(30) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (5); and R² is the same as that defined in the above item(10), or salt thereof.

(31) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (11); and R² is the same as that defined in the aboveitem (10), or salt thereof.

(32) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (12); and R² is the same as that defined in the aboveitem (10) or salt thereof.

(33) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (1); and R² is the same as that defined in the above item(11), or salt thereof.

(34) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (2); and R² is the same as that defined in the above item(11), or salt thereof.

(35) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (5); and R² is the same as that defined in the above item(11), or salt thereof.

(36) A fluorenone derivative-wherein R¹ is the same as that defined inthe above item (10); and R² is the same as that defined in the aboveitem (11), or salt thereof.

(37) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (12); and R² is the same as that defined in the aboveitem (11), or salt thereof.

(38) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (1); and R² is the same as that defined in the above item(12), or salt thereof.

(39) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (2); and R² is the same as that defined in the above item(12), or salt thereof.

(40) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (5); and R² is the same as that defined in the above item(12), or salt thereof.

(41) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (10); and R² is the same as that defined in the aboveitem (12), or salt thereof.

(42) A fluorenone derivative wherein R¹ is the same as that defined inthe above item (11); and R² is the same as that defined in the aboveitem (12), or salt thereof.

The fluorenone derivative represented by the formula (1) may be producedby various methods, for example, it is easily produced by a method shownin the following reaction scheme. ##STR18## wherein R¹, R², p and q areas defined above!.

The cyclization reaction of introducing the compound (2) to the compound(1) can be conducted by various cyclization reactions which havehitherto been known. Examples thereof include a method due to heating, acyclization method using acidic substances such as phosphorousoxychloride, phosphorous pentachloride, phosphorous trichloride, thionylchloride, concentrated sulfuric acid, polyphosphoric acid and the like.When employing the cyclization method due to heating, high boiling pointhydrocarbons and high boiling point ethers, e.g. solvents such astetralin, diphenyl ether, diethylene glycol dimethyl ether and the likeare used. Normally, the heating condition of 100 to 250° C., preferably150 to 200° C. can be employed. When employing the cyclization methodusing the acidic substance, the proportion of the acidic substance tothe compound (2) is normally in a range from an equimolar amount to anexcessive amount, preferably from 10- to 20-time molar amount. Normally,the reaction may be conducted at a temperature from room temperature to150° C. for about 0.1 to 6 hours. In case of the cyclization methodusing the acidic substance, the reaction may be conducted under theabsence or presence of a suitable solvent. As the solvent, there can beused any one as far as it exerts no influence upon the reaction, andexamples thereof include ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme, diglyme, etc.; acid anhydrides such asacetic anhydride, etc.; aliphatic hydrocarbons such as n-hexane,heptane, ligroin, etc,; halogenated hydrocarbons such as chloroform,methylene chloride, carbon tetrachloride, etc.; aprotic polar solventssuch as dimethylformamide, dimethyl sulfoxide, hexamethylphosphorictriamide, etc.

The compound (2) used as a starting material can be produced by a methodshown in the following reaction scheme-2. ##STR19## wherein R¹, R², pand q are as defined above; R³ is a lower alkoxy group; X is a halogenatom; and R⁴ and R⁵ are the same or different and indicate a lower alkylgroup!.

The reaction between the compound (3) and the compound (4) is conductedin a suitable solvent. As the solvent, there can be any one which isused in a Grignard reaction. Preferred examples thereof include etherssuch as diethyl ether, dioxane, tetrahydrofuran, etc.; aromatichydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons suchas pentane, hexane, heptane, cyclohexane, etc. The proportion of thecompound (4) to the compound (3) is normally at least an equimolaramount, preferably in a range from an equimolar amount to 2-time molaramount. The above reaction is normally conducted at a temperature fromabout -70 to 50° C., preferably from -30° C. to room temperature.Normally, it is completed for about 1 to 50 hours.

The reaction of introducing the compound (5) to the compound (2) isconducted by alkylating the compound (5) in a suitable solvent in thepresence of an alkylating agent and hydrolyzing the resulting compound.

As the alkylating agent used for alkylating the compound (5), forexample, there is a halogenated alkyl such as methyl iodide and thelike. The alkylation is normally conducted at a temperature from roomtemperature to 200° C., preferably from room temperature to 150° C.Normally, it is completed for about 1 to 30 hours. Examples of thesolvent include ethers such as dioxane, tetrahydrofuran, ethylene glycoldimethyl ether, diethyl ether, etc.; aromatic hydrocarbons such asbenzene, toluene, xylene, etc.; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, etc.; lower alcoholssuch as methanol, ethanol, isopropanol, etc.; polar solvents such asdimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide,acetone, acetonitrile, nitromethane and the like. The proportion of thealkylating agent to the compound (5) is normally at least an equimolaramount, preferably in a range from an equimolar amount to 8-time molaramount.

In the following hydrolyzation reaction, any reaction conditions of thenormal hydrolyzation can be applied. For example, the hydrolyzationreaction is conducted in a solvent (e.g. water, alcohols such asmethanol, ethanol, isopropyl alcohol, etc.; ketones such as acetone,methyl ethyl ketone, etc.; ethers such as dioxane, ethylene glycoldimethyl ether, etc. or a mixed solvent thereof) under the presence ofbasic compounds such as sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide, barium hydroxide and the like. Thereaction is normally conducted at a temperature from room temperature to200° C., preferably from room temperature to 150° C. Normally,it iscompleted for about 0.5 to 20 hours.

The compound (2) can also be obtained by hydrolyzing (under the samecondition as that of the above hydrolyzation, e.g. a kind of solvent,reaction temperature and reaction time) under the presence of mineralacids such as sulfuric acid, hydrochloric acid, nitric acid, etc.;organic acids such as acetic acid, aromatic sulfonic acid, etc.##STR20## wherein R¹, R² and p are as defined above; R^(8a) and R^(9a)are the same or different and indicate a hydrogen atom or a lower alkylgroup; and r is an integer of 1 to 3; provided that r is 1 or 2 when R²is a substituent other than a hydrogen atom!

The reaction between the compound (1a) and the compound (6) is referredto as a Mannich reaction and is conducted in a suitable solvent underthe presence of formaldehyde and acid or absence of acid. As thesolvent, there can be any one which is normally used in the Mannichreaction. Examples thereof include water, alcohols such as methanol,ethanol, isopropanol, etc.; alkane acids such as acetic acid, propionicacid, etc.; acid anhydrides such as acetic anhydride, etc.; polarsolvents such as acetone, dimethylformamide, etc; or a mixed solventthereof. Examples of the acid include mineral acids such as hydrochloricacid, hydrobromic acid, etc.; organic acids such as acetic acid, etc. Asthe formaldehyde, for example, there can be normally used an aqueoussolution, trimer and polymer (paraformaldehyde) containing 20 to 40% byweight of formaldehyde.

The proportion of the compound of the formula (6) to the compound of theformula (1a) is normally at least an equimolar amount, preferably anequimolar amount to 5-time molar amount. The proportion of formaldehydeto the compound of the formula (1a) is normally at least an equimolaramount, preferably in a range from an equimolar amount to 5-time molaramount. The reaction is normally conducted at a temperature from 0 to200° C., preferably from room temperature to 150° C. Normally, it iscompleted for about 0.5 to 30 hours. ##STR21## wherein R¹, R² R^(8a)R^(9a), q and r are as defined above; provided that r is 1 or 2 when R¹is a substituent other than a hydrogen atom!.

The reaction between the compound (1c) and the compound (6) can beconducted under the same condition as that between the compound (1a) andthe compound (6) according to the above reaction scheme-3. ##STR22##wherein R¹, R², p, r and X are as defined above; R¹⁰, R¹¹ and R¹²indicate a lower alkyl group; and R¹³ is a group of the formula:##STR23## (R⁸ and R⁹ are as defined above), an imidazolyl group or alower alkoxy group!.

The reaction between the compound (1e) and the compound (7) can beconducted in a suitable inert solvent under the presence or absence ofbasic compounds.

Examples of the inert solvent include aromatic hydrocarbons such asbenzene, toluene, xylene, etc.; ethers such as tetrahydrofuran, dioxane,diethylene glycol dimethyl ether, etc.; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, etc.; lower alcoholssuch as methanol, ethanol, isopropanol, butanol, tert-butanol, etc.;acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide or a mixedsolvent thereof.

Examples of the basic compound include carbonates such as sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonates, etc.; metallic hydroxides such as sodium hydroxide,potassium hydroxide, etc.; metallic alcoholates such as sodium hydride,potassium, sodium, sodium amide, sodium methylate, sodium ethylate,etc.; organic bases such as pyridine, N-ethyldiisopropylamine,dimethylaminopyridine, triethylamine, 1,5-diazocyclo 4.3.0!nonene-5(DBN), 1,8-diazabicyclo 5.4.0!undecene-7 (DBU), 1,4-diazabicyclo2.2.2!octane (DABCO) and the like. The proportion of the compound (7) tothe compound (1e) is not limited to a specific value, and may vary overa wide range. The proportion of the latter to the former is normally atleast an equimolar amount, preferably in a range from an equimolaramount to 15-time molar amount. The reaction is normally conducted at atemperature from about 0 to 200° C., preferably from 0 to 170° C.Normally, it is completed for about 30 minutes to 75 hours. ##STR24##wherein R¹, R², q, r, R¹⁰, R¹¹, R¹² and X are as defined above; R¹⁴ is agroup of the formula: ##STR25## (R⁸ and R⁹ are as defined above), animidazolyl group, a lower alkoxy group or a hydroxyl group-substitutedlower alkoxy-lower alkoxy group!.

The reaction between the compound (1g) and the compound (8) can beconducted under the same condition as that between the compound (1c) andthe compound (7) according to the above reaction scheme-5. ##STR26##wherein R¹, R², p, q, r, R^(8a) and R^(9a) are as defined above!.

The reaction of introducing the compound (1i) to the compound (1j) andthe reaction of introducing the compound (1k) to the compound (11) areconducted in the presence or absence of a suitable solvent under thepresence of catalytic reducing agents and hydrogen donors. Examples ofthe solvent include water, alcohols such as methanol, ethanol,isopropanol, etc.; organic acids such as formic acid, acetic acid, etc.;esters such as ethyl acetate etc.; ethers such as dioxane, diglyme,tetrahydrofuran, etc.; aromatic hydrocarbons such as benzene, toluene,xylene, etc. or a mixed solvent thereof. Examples of the catalyticreducing agent include palladium black, palladium-carbon, platinumoxide, platinum black, Raney nickel and the like.

Examples of the hydrogen donor include formic acid, ammonium formate,cyclohexene, hydrazine hydrate and the like. The reaction is normallyconducted at a temperature from about 0 to 150° C., preferably from 0 to100° C. Normally, it is completed for about 5 minutes to 12 hours. Theamount of the catalytic reducing agent to the compound (1i) or (1k) isnormally about 0.01 to 40% by weight, preferably 0.01 to 20% by weight.The proportion of the hydrogen donor to the compound (1i) or (1k) isnormally at least an equimolar amount, preferably in a range from anequimolar amount to 10-time molar amount. ##STR27## wherein R¹, R².sub.,p, r, R^(8a) and R^(9a) are as defined above; and R¹⁵ is a pyridylthiogroup, a phenylthio group optionally containing a lower alkoxy group asa substituent on a phenyl ring, a benzimidazolylthio group, animidazolylthio group or a cycloalkylthio group!.

The reaction between the compound (1i) and the compound (9) can beconducted under the same condition as that between the compound (1e) andthe compound (7) according to the above reaction scheme-5.

The compound (1) wherein at least one of R¹ and R² is a lower alkoxygroup can be introduced to the corresponding compound (1) wherein atleast one of R¹ and R² is a hydroxyl group by heating to 30 to 150° C.,preferably 50 to 120° C., in a mixture of acids such as hydrobromicacid, hydrochloric acid, etc. and solvents such as acetic acid, etc. Thecompound wherein at least one of R¹ and R² is a lower alkoxy group canalso be introduced to the corresponding compound (1) wherein at leastone of R¹ and R² is a hydroxyl group by the hydrolyzation. Thehydrolyzation is conducted in a suitable solvent under the presence ofacids. Examples of the solvent include ethers such as dioxane,tetrahydrofuran, etc.; halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride, etc.; aromatic hydrocarbons such asbenzene, toluene, xylene, etc.; polar solvents such as acetonitrile,etc.; and a mixed solvent thereof. Examples of the acid include Lewisacids such as boron trioxide, aluminium chloride, boron tribromide,etc.; iodides such as sodium iodide, potassium iodide, etc. or a mixtureof Lewis acids and iodides and the like. The reaction is normallyconducted at a temperature from room temperature to 150° C., preferablyfrom room temperature to 100° C. Normally, it is completed for about 0.5to 15 hours.

The compound (1) wherein at least one of R¹ and R² is a lower alkenyloxygroup may be produced by reacting the corresponding compound (1) whereinat least one of R¹ and R² is a hydroxyl group with the compoundrepresented by the formula: R⁶ X (10) (wherein R⁶ is a lower alkenylgroup; and X is as defined above). The reaction is conducted in asuitable solvent under the presence of basic compounds. Examples of thesolvent include water, lower alcohols such as Examples of the solventinclude water, lower alcohols such as methanol, ethanol, propanol, etc.;ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycolmonomethyl ether, aromatic hydrocarbons such as benzene, toluene,xylene, etc.; esters such as methyl acetate, ethyl acetate, etc.;ketones such as acetone, methyl ethyl ketone, etc.; polar solvents suchas acetonitrile, dimethylformamide, dimethyl sulfoxide,hexamethylphosphoric triamide, etc.; or a mixed solvent thereof.Examples of the basic compound include inorganic bases such as sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium bicarbonate, potassium bicarbonate, sodium hydride, etc.; alkalimetals such as metallic sodium, metallic potassium, etc.; alkali metalalcoholates such as sodium ethylate, sodium methylate, etc.; organicbases such as triethylamine, pyridine, N,N-dimetylaniline,N-methylmorpholine, 4-methylaminopyridine, 1,5-diazabicyclo4.3.0!nonene-5 (DBN), 1,8-diazabicyclo 5.4.0!undecene-7 (DBU),1,4-diazabicyclo 2.2.2!octane (DABCO) and the like. The proportion ofthe compound (10) to the compound (1) is normally at least an equimolaramount, preferably in a range from an equimolar amount to 5-time molaramount. The reaction is normally conducted at a temperature from about 0to 150° C., preferably from room temperature to 100° C. Normally, it iscompleted for about 0.5 to 20 hours.

The compound (1) wherein at least two of R¹ and R² is a lower alkenylgroup and a hydroxyl group may be produced by subjecting thecorresponding compound (1) wherein at least one of R¹ and R² is a loweralkenyloxy group to a Claisen rearrangement reaction. The Claisenrearrangement reaction is conducted by heating in a suitable solvent.Examples of the solvent include high boiling point solvents such asdimethylformamide, tetrahydronaphthalene, N,N-dimethylaniline,N,N-diethylaniline, diphenyl ether and the like. The reaction isnormally conducted at a temperature from 100 to 250° C., preferably from150 to 250° C. Normally, it is completed for about 1 to 30 hours.

The compound (1) wherein at least one of R¹ and R2 is a lower alkylgroup may be produced by reducing the corresponding compound (1) whereinat least one of R¹ and R² is a lower alkenyl group. The reductionreaction is conducted by catalytically reducing in a suitable solventunder the presence of catalysts. Examples of the solvent includealcohols such as water, acetic acid, methanol, ethanol, isopropylalcohol, etc.; hydrocarbons such as hexane, cyclohexane, etc.; etherssuch as diethylene glycol dimethyl ether, dioxane, tetrahydrofurandiethyl ether, etc.; esters such as ethyl acetate, methyl acetate, etc.;polar solvents such as dimethylformamide, etc.; or a mixed solventthereof. Examples of the catalyst include palladium, palladium black,palladium-carbon, platinum, platinum oxide, copper chromite, Raneynickel and the like. The proportion of the catalyst to the compound (1)is normally in a range from about 0.02- to 1-time molar amount. Thereaction temperature is normally about -20 to 100° C., preferably 0 to70° C., and the hydrogen pressure is preferably 1 to 10 atoms. Normally,the reaction is completed for about 0.5 to 20 hours.

The compound (1) wherein at least one of R¹ and/or R² is a halogen atommay be produced by halogenating the corresponding compound (1) whereinat least one of R¹ and R² is a hydrogen atom. The halogenation reactionis conducted in a suitable solvent under the presence of halogenatingagents. Examples of the halogenating agent include halogen moleculessuch as bromine, chlorine, etc.; N-succinimide halides such as iodinechloride, sulfuryl chloride, N-bromosuccinimide, N-chlorosuccinimide,etc. The proportion of the halogenating agent to the compound (1) isnormally in a range from an equimolar amount to 20-time molar amount,preferably from an equimolar amount to 10-time molar amount. Examples ofthe solvent include halogenated hydrocarbons such as dichloromethane,dichloroethane, chloroform, carbon chloride, etc.; fatty acids such asacetic acid, propionic acid, etc. The reaction is normally conducted ata temperature from about 0° C. to a boiling point of the solvent,preferably from 0 to 50° C. Normally, it is completed for about 0.5 to20 hours.

In case of the compound (1) wherein at least one of R¹ and R² is ahydroxyl group, the compound (1) can be introduced to the compound (1)wherein at least one of R¹ and R² is a lower alkanoyloxy group bysubjecting to lower alkanoylation reaction, using the compoundrepresented by the formula: (R⁷)₂ O (11) or R⁷ X (12) (wherein R⁷ is alower alkanoyl group; and X is as defined above). The loweralkanoylation reaction is conducted under the presence or absence ofbasic compounds. Examples of the basic compound include alkali metalssuch as metallic sodium, metallic potassium, etc. and hydroxides,carbonates or bicarbonates of alkali metals; organic bases such asN,N-dimethylaminopyridine, pyridine, piperidine, etc. The reaction canbe conducted in the presence or absence of a solvent. Examples of thesolvent include ketones such as acetone, methyl ethyl ketone, etc.;ethers such as diethyl ether, dioxane, etc.; aromatic hydrocarbons suchas benzene, toluene, xylene, etc.; water, pyridine and the like. Theproportion of the compound (11) or (12) to the starting material isnormally at least an equimolar amount, preferably in a range from anequimolar amount to an excessive amount. The reaction is normallyconducted at a temperature from about 0 to 200° C., preferably from 0 to150° C. Normally, the reaction time is about 5 minutes to 5 days.

The objective product thus obtained in each process can be easilyseparated by a normal separating means, and further purified. Examplesof the separating means include solvent extraction, dilution,recrystallization, column chromatography, preparative thin-layerchromatography and the like.

In the fluorenone derivatives represented by formula (1), compoundhaving ammonium group may be easily reacted with halogen anion(such aschlorine anion, bromine anion, iodine anion, etc.) to form a salt.

As a matter of course, the compound of the present invention includesstereoisomers and optical isomers.

The compound of the present invention may be normally used in the formof a general pharmaceutical composition. The pharmaceutical compositionmay be prepared using diluents or excipients such as filler, extender,binder, humidifying agent, disintegrator, surfactant, lubricant and thelike which may be normally used. According to the curing purpose, thepharmaceutical composition may be made in any forms such as tablet,pill, powder, liquid preparation, suspension, emulsion, granule,capsule, suppository, injection (e.g. liquid preparation, suspension,etc.), ointment and the like. When molding the pharmaceuticalcomposition in the form of tablet, there can be widely used any carriersconventionally used in this field. Examples of the carrier includeexcipients such as lactose, white sugar, sodium chloride, glucose, urea,starch, calcium carbonate, kaoline, crystal cellulose, silica, etc.;binders such as water, ethanol, propanol, simple syrup, glucose liquid,starch liquid, gelatin solution, carboxymethyl cellulose, shellac,methyl cellulose, potassium phosphate, polyvinyl pyrrolidone, etc.;disintegrators such as dry starch, sodium alginate, agar powder,laminaria powder, sodium bicarbonate, calcium carbonate, polyoxyethylenesorbitan fatty esters, sodium lauryl sulfate, monoglyceride stearate,starch, lactose, etc.; disintegration restraining agents such as whitesugar, stearin, cacao butter, hydrogenated oil, etc.; absorptionaccelerating agents such as quaternary ammonium base, sodium laurylsulfate, etc.; humectants such as glycerin, starch, etc.; absorbentssuch as starch, lactose, kaoline, bentonite, colloidal silicic acid,etc.; lubricants such as purified talc, salt stearate, boric acidpowder, polyethylene glycol, etc. If necessary, tablets may be coatedwith a normal film to prepare sugar-coated tablets, gelatin-coatedtablets, enteric-coated tablets, film-coated tablets or tabletscomprising two or more layers. When molding the pharmaceuticalcomposition in the form of pill, there can be widely used any carriersknown in this field. Examples of the carrier include excipients such asglucose, lactose, starch, cacao butter, hydrogenated vegetable oil,kaoline, talc, etc.; binders such as powdered acacia gum, powderedtraganth, gelatin, ethanol, etc; and disintegrators such as laminaria,agar, etc. When molding the pharmaceutical preparation in the form ofsuppository, there can be widely used any known carriers. Example of thecarrier include esters such as polyethylene glycol, cacao butter, higheralcohol, etc.; gelatin and semisynthetic glyceride. When preparing thepharmaceutical composition in the form of injection, the resultingsolution, emulsion and suspension are preferably sterilized and madeisotonic with respect to the blood. When preparing the pharmaceuticalcomposition in the form of solution, emulsion and suspension, there canbe used any diluents generally used in this field. Examples of thediluent include water, aqueous lactose, ethyl alcohol, propylene glycol,ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,polyoxyethylene sorbitan fatty esters and the like. The pharmaceuticalcomposition may contain salt, glucose or glycerin in an amountsufficient to prepare an isotonic solution. There can also be addedsolubilizers, buffer agents, pain-alleviating agents and the like. Ifnecessary, the pharmaceutical composition may contain colorants,preservatives, perfumes, flavors, sweeteners, other pharmaceuticalproducts and the like. When molding the pharmaceutical composition inthe form of paste, cream or gel, there can be widely used knowndiluents. Example of the diluent include white soft paraffine,paraffine, glycerin, cellulose derivative, polyethylene glycol, silicon,bentonite and the like.

The amount of the compound of the formula (1) or a salt thereof to beformulated in the pharmaceutical composition is not limited to aspecific one but may be vary over a wide range. It is preferably 1 to70% by weight based on the weight of the pharmaceutical composition.

The administration method of the above pharmaceutical composition is notspecifically limited and can be selected according to the form of thepreparation, patient's age and gender, other conditions, symptoms ofdiseases and the like. For example, the pills, liquids, suspensions,emulsions, granules and capsules are orally administered. The injectionsare intravenously administered either alone or together with ordinaryauxiliary agents such as glucose, amino acid and the like. Further, theinjections may be singly administered intramuscularly, intracutaneously,subcutaneously or intraperitoneally, if necessary. The suppository isadministered intrarectally.

The dosage of the pharmaceutical composition is suitably selectedaccording to the purpose of use, patient's age and gender, symptoms ofdiseases and the like. Normally, it is preferred that the compound ofthe formula (1) or a salt thereof as the active component isadministered per day with a dairy dose of about 0.2 to 200 mg/kg.

The following Preparation Examples, Reference Examples, Examples andPharmacological tests further illustrate the present invention in detailbut are not to be construed to limit the scope thereof.

    ______________________________________                                        Preparation Example 1                                                         ______________________________________                                        1,6-Diallyl-2,7-dihydroxyfluorenone                                                                   5           mg                                        Starch                  132         mg                                        Magnesium stearate      18          mg                                        Lactose                 45          mg                                        Total                   200         mg                                        ______________________________________                                    

According to a normal method, a tablet of the above composition wasproduced.

    ______________________________________                                        Preparation Example 2                                                         ______________________________________                                        1,6-Diallyl-2,5-dihydroxyfluorenone                                                                   150         mg                                        Avicel (tradename, manufactured                                                                       40          g                                         by Asahi Kasei Co., Ltd.)                                                     Cornstarch              30          g                                         Magnesium stearate      2           g                                         Hydroxypropyl methyl cellulose                                                                        10          g                                         Polyethylene glycol 6000                                                                              3           g                                         Castor oil              40          g                                         Methanol                40          g                                         ______________________________________                                    

The compound of the present invention, Avicel, cornstarch and magnesiumstearate are mixed and abraded, and the mixture is compressed by a punchwith a sugar-coat R (10 mm). The resulting tablets are coated with afilm-coating agent comprising hydroxypropyl methyl cellulose,polyethylene glycol 6000, castor oil and methanol to produce film-coatedtablets.

REFERENCE EXAMPLE 1

In tetrahydrofuran (100 ml), magnesium (1.3 g) was reacted with4-bromoveratrole (13 g) to prepare a Grignard reagent. While cooling inan ice-water bath, a solution of2-(2,4,5-trimethoxyphenyl)-4,4-dimethyl-2-oxazoline (7.7 g) intetrahydrofuran (100 ml) was added thereto. After stirring at roomtemperature for 48 hours, an aqueous saturated ammonium chloridesolution (150 ml) was added and stirred for 15 minutes. Then, the mixedsolution was separated to extract the aqueous layer with tetrahydrofuran(150 ml). The organic layers were combined each other and concentratedby an evaporator. The residue was dissolved in 10% hydrochloric acid(100 ml), which was washed with diethyl ether. The aqueous layer wascooled in an ice-water bath, then neutralized by adding a 20% aqueoussodium hydroxide solution. It was extracted with ethyl acetate, washedwith a saturated saline solution and then dried over sodium sulfate. Thesolvent was distilled off to give 10 g of 2-2-(3,4-dimethoxyphenyl)-4,5-dimethoxyphenyl!-4,4-dimethyl-2-oxazoline asa pale brown oil.

¹ H-NMR (CDCl₃)δ ppm; 1.31 (6H, s), 3.79 (2H, s), 3.89 (3H, s), 3.92(6H, s), 3.92 (3H, s), 6.83 (1H, s), 6.88-6.96 (3H, m), 7.25 (1H, s)

REFERENCE EXAMPLE 2

2- 2-(3,4-Dimethoxyphenyl)-4,5-dimethoxyphenyl!-4,4-dimethyl-2-oxazoline(10 g) was dissolved in nitromethane (100 ml), to which was added methyliodide (10 ml), and the mixture was allowed to stand at room temperaturefor 24 hours. It was concentrated by an evaporator, and methanol (150ml) and a 20% aqueous sodium hydroxide solution (150 ml) were added tothe residue to reflux for 18 hours. The solvent was distilled off untilthe system becomes ununiform, and water was added until it becomestransparent. After washing with diethyl ether (200 ml), the aqueouslayer was cooled in a ice-water bath and concentrated hydrochloric acidwas added until it becomes acidic. The insoluble matter formed wasfiltered, washed with water and dried to give 7.7 g of2-(3,4-dimethoxyphenyl)-4,5-dimethoxybenzoic acid as a white powder.

By using a suitable starting material, compounds shown in Table 1 wereobtained according to the same manner as that described in ReferenceExample 1.

                                      TABLE 1                                     __________________________________________________________________________    1 #STR28##                                                                    Reference                                                                     Example                                                                            (R.sup.1).sub.p                                                                      (R.sup.2).sub.q                                                                       R.sup.4                                                                          R.sup.5                                                                          Physical properties                                 __________________________________________________________________________     3   4-OCH.sub.3                                                                          2 #STR29##                                                                            CH.sub.3                                                                         CH.sub.3                                                                         colorless prism-like crystals (n-hexane-ethyl                                 acetate) mp. 89.0-90.0° C.                    4   3-OCH.sub.3                                                                          H       CH.sub.3                                                                         CH.sub.3                                                                         pale yellow oily                                     5   2-OCH.sub.3                                                                          H       CH.sub.3                                                                         CH.sub.3                                                                         colorless oily                                       6   4-OCH.sub.3                                                                          H       CH.sub.3                                                                         CH.sub.3                                                                         pale yellow oily                                     7   3-SCH.sub.3                                                                          H       CH.sub.3                                                                         CH.sub.3                                                                         pale yellow oily                                         6-OCH.sub.3                                                               8   4-OCH.sub.3                                                                          4-OCH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                         pale yellow oily                                     9   4-OCH.sub.3                                                                          5-OCH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                         colorless prism-like crystals                                                 (n-hexane-diethyl ether)                                                      mp. 65.0-66.0° C.                            10   4-OCH.sub.3                                                                          6-OCH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                         colorless needle-like crystals                                                (n-hexane-diethyl ether)                                                      mp. 83.5-84.5° C.                            11   4-OCH.sub.3                                                                          3-OCH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                         colorless prism-like crystals                                                 (n-hexane)                                                                    mp. 69.0-70.0° C.                            12   H      3-OCH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                         colorless prism-like crystals                                                 (n-hexane-diethyl ether)                                                      mp. 67.0-68.0° C.                            13   3-OCH.sub.3                                                                          H       CH.sub.3                                                                         CH.sub.3                                                                         pale yellow oily                                         4-OCH.sub.3                                                              14                                                                                 3 #STR30##                                                                           3-OCH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                         pale yellow oily                                    15   3-OCH.sub.3                                                                          3-OCH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                         pale yellow oily                                         4-OCH.sub.3                                                              16   4-OCH.sub.3                                                                          4-OCH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                         pale yellow oily                                                5-OCH.sub.3                                                       __________________________________________________________________________

COMPOUND OF REFERENCE EXAMPLE 4

¹ H-NMR (CDCl₃, δ ppm); 1.29 (6H, s), 3.81 (2H, s), 3.83 (3H, s), 6.88(1H, dd, J=1 Hz, J=5.5 Hz), 6.90-7.01 (2H, m), 7.29-7.70 (4H, m), 7.72(1H, dd, J=1 Hz, J=6.5 Hz).

COMPOUND OF REFERENCE EXAMPLE 5

1H-NMR (CDCl₃, δ ppm); 1.25 (6H, s), 3.73 (3H, s), 3.75 (2H, s), 6.89(1H, d, J=8 Hz), 7.00 (1H, ddd, J=1 Hz, J=7.5 Hz, J=7.5 Hz), 7.24 (1H,dd, J=1.5 Hz, J=7.5 Hz), 7.28-7.39 (3H, m), 7.47 (1H, ddd, J=1.5 Hz,J=7.5 Hz, J=7.5 Hz), 7.84 (1H, dd, J=1.5 Hz, J=7.5 Hz).

COMPOUND OF REFERENCE EXAMPLE 6

¹ H-NMR (CDCl₃, δ ppm); 1.31 (6H, s), 3.82 (2H, s), 3.84 (3H, s),6.89-6.95 (2H, m), 7.29-7.30 (4H, m), 7.46 (1H, ddd, J=1.5 Hz, J=7.5 Hz,J=7.5 Hz), 7.70 (1H, dd, J=1.5 Hz, J=7.5 Hz).

COMPOUND OF REFERENCE EXAMPLE 7

¹ H-NMR (CDCl₃, δ ppm); 1.26 (6H, s), 3.46 (3H, s), 3.72 (3H, s), 3.77(2H, s), 6.84 (1H, d, J=8.5 Hz), 7.20-7.40 (4H, m), 7.48 (1H, ddd, J=1.5Hz, J=7.5 Hz, J=7.5 Hz), 7.84 (1H, dd, J=1.5 Hz, J=7.5 Hz).

COMPOUND OF REFERENCE EXAMPLE 8

¹ H-NMR (CDCl₃, δ ppm); 1.29 (6H, s), 3.79 (2H, s), 3.85 (6H, s),6.83-6.95 (4H, m), 7.29-7.35 (2H, m), 7.65-7.69 (1H, m).

COMPOUND OF REFERENCE EXAMPLE 8

¹ H-NMR (CDCl₃, δ ppm); 1.29 (6H, s), 3.79 (2H, s), 3.85 (6H, s),6.83-6.95 (4H, m), 7.29-7.35 (2H, m), 7.65-7.69 (1H, m).

COMPOUND OF REFERENCE EXAMPLE 13

¹ H-NMR (CDCl₃, δ ppm); 1.30 (6H, s), 3.83 (2H, s), 3.89 (3H, s), 3.92(3H, s), 6.88-6.99 (3H, m), 7.31-7.51 (3H, m), 7.69-7.74 (1H, m).

COMPOUND OF REFERENCE EXAMPLE 14

¹ H-NMR (CDCl₃, δ ppm); 1.22 (6H, s), 1.36 (6H, d, J=6 Hz), 3.72 (2H,s), 3.76 (3H, s), 4.58 (1H, sept, J=6 Hz), 6.85-6.92 (2H, m), 7.03 (1H,dd, J=2 Hz, J=7.5 Hz), 7.20-7.34 (4H, m).

COMPOUND OF REFERENCE EXAMPLE 15

¹ H-NMR (CDCl₃, δ ppm); 1.22 (6H, s), 3.71 (2H, s), 3.78 (3H, s), 3.86(3H, s), 3.89 (3H, s), 6.87-6.91 (3H, m), 7.04 (1H, dd, J=2.5 Hz, J=9.0Hz), 7.27-7.36 (2H, m).

COMPOUND OF REFERENCE EXAMPLE 16

¹ H-NMR (CDCl₃, δ ppm); 1.31 (6H, s), 3.79 (2H, s), 3.85 (3H, s), 3.91(3H, s), 3.95 (3H, s), 6.82 (1H, s), 6.90 (2H, d, J=9.0 Hz), 7.24 (1H,s), 7.30 (2H, d, J=9.0 Hz).

By using a suitable starting material, compounds shown in Tables 2 wereobtained according to the same manner as that described in ReferenceExample 2.

                  TABLE 2                                                         ______________________________________                                        4 #STR31##                                                                    Reference                                                                     Example                                                                              (R.sup.1).sub.p                                                                          (R.sup.2).sub.q                                                                       Physical properties                                 ______________________________________                                        17     4-OCH.sub.3                                                                              3-OCH.sub.3                                                                           colorless needle-like crystals                                                (chloroform) mp. 171.0-173.0° C.             18     4-OCH.sub.3                                                                              5-OCH.sub.3                                                                           colorless prism-like crystals                                                 (ethanol) mp. 153.0-155.0° C.                19     4-OCH.sub.3                                                                              4-OCH.sub.3                                                                           colorless particulate crystals                                                (ethanol) mp. 169.0-172.0° C.                20     3-OCH.sub.3                                                                              H       colorless prism-like crystals                              4-OCH.sub.3        (ethyl acetate)                                                               mp. 165.0-167.0° C.                          21     H          3-OCH.sub.3                                                                           colorless prism-like crystals                                                 (ethyl acetate)                                                               mp. 177.0-179.0° C.                          22     4-OCH.sub.3                                                                              6-OCH.sub.3                                                 23                                                                                   3 #STR32## 3-OCH.sub.3                                                                           colorless powdered mp. 126-127.0° C.         24     2-OCH.sub.3                                                                              H       colorless powdered                                                            (n-hexane-ethyl acetate)                                                      mp. 150.0-152.0° C.                          25     3-OCH.sub.3                                                                              H       brown oil                                           26     4-OCH.sub.3                                                                              H       colorless powdered crystals                                                   mp. 143.0-145.0° C.                                                    (decomposed)                                        27     3-OCH.sub.3                                                                              3-OCH.sub.3                                                                           white powdered                                             4-OCH.sub.3                                                            28     4-OCH.sub.3                                                                              4-OCH.sub.3                                                                           pale brown powdered                                                   5-OCH.sub.3                                                                           mp. 194.0-195.0° C.                          ______________________________________                                    

COMPOUND OF REFERENCE EXAMPLE 25

¹ H-NMR (CDCl₃, δ ppm); 3.80 (3H, s), 6.87-6.93 (3H, m), 7.24-7.58 (3H,m), 7.54 (1H, ddd, J=1.5 Hz, J=7.5 Hz, J=7.5 Hz), 7.92 (1H, dd, J=1.5Hz, J=7.5 Hz), 9.83 (1H, s).

By using a suitable starting material, the following compound wasobtained according to the same manner as that described in ReferenceExample 1.

                  TABLE 3                                                         ______________________________________                                        5 #STR33##                                                                    Refer-                                                                        ence                                                                          Exam-                                                                         ple   (R.sup.1).sub.p                                                                          (R.sup.2).sub.q                                                                       R.sup.4                                                                            R.sup.5                                                                            Physical properties                        ______________________________________                                        29                                                                                  6 #STR34## 3-OCH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           .sup.1 H-NMR (CDCl.sub.3, δ                                             ppm); 1.14(6H, s), 1.23(6H, d,                                                J=2.3Hz), 1.25(6H, d, J=2.6Hz),                                               3.28-3.39(2H, m), 3.75(3H, s),                                                3.77(3H, s), 7.00-7.05(3H, m),                                                7.25-7.35(2H, m)                           ______________________________________                                    

EXAMPLE 1

Polyphosphoric acid which had been newly prepared from diphosphoruspentaoxide (50 g) and phosphoric acid (50 ml) was heated at 100° C. Withstirring, 2-(3,4-dimethoxyphenyl)-4,5-dimethoxybenzoic acid (7.5 g) wasadded thereto as it is (in the crystal form) in several portions. Afterstirring at 100 to 120° C. for 2 hours, the reaction solution was pouredinto water (1.5 liter) and extracted with chloroform. The extract waswashed with 2% aqueous sodium hydroxide solution, water and a saturatedsaline solution, then dried over sodium sulfate. The solvent wasdistilled off, and the residue was purified by silica gel columnchromatography (eluent: chloroform) and recrystallized from ethylacetate-n-hexane to give 5.0 g of 2,3,6,7-tetramethoxyfluorenone as anorange needle-like crystal.

Melting point: 194.0-195.0° C.

EXAMPLE 2

To a mixed solution of acetic acid (20 ml) and 47% hydrobromic acid (10ml), 2,3,6,7-tetramethoxyfluorenone (8.0 g) was added and the mixturewas refluxed for 15 hours. After cooling, the precipitated crystals werefiltered, washed with water and then recrystallized fromwater-containing ethanol to give 5.0 g of 2,3,6,7-tetrahydroxyfluorenoneas a claret powder.

Melting point: more than 300° C.

¹ H-NMR (DMSO-d₆) δ ppm; 6.83 (4H, s), 9.33 (2H, bs), 9.79 (2H, bs)

By using a suitable starting material, compounds of the Examples 9 to24, 26 to 65, 68, 69, 81, 86, 89, 91, 105, 109, 110, 112 to 133, 135 to147 and 152 were obtained according to the same manner as that describedin Example 2.

EXAMPLE 3

2,3-Dimethoxyfluorenone (15 g) was dissolved in toluene (300 ml), towhich was added anhydrous aluminum chloride (20 g) and the mixture wasstirred at 90° C. for 2 hours. After cooling, the reaction solution waspoured into ice water (1.5 liter). Then, the insoluble matter formed wasfiltered, washed with water, dried and recrystallized from ethyl acetateto give 9.8 g of 2,3-dihydroxyfluorenone as a yellow needle-likecrystal.

Melting point: 247.0-248.0° C.

By using a suitable starting material, compounds of the Examples 9 to19, 21 to 65, 68, 69, 81, 86, 89, 91, 105, 109, 110, 112 to 133, 135 to147 and 152 were obtained according to the same manner as that describedin Example 3.

EXAMPLE 4

To dimethylformamide (200 ml), 2,3-dihydroxyfluorenone (9.8 g) andpotassium carbonate (15 g) were added and the mixture was stirred atroom temperature for 30 minutes. To this was added allyl bromide (10ml), followed by stirring at room temperature for 15 hours. The solventwas distilled off by an evaporator and water was added to the residue,which was extracted with ethyl acetate. The extract was washed withwater and a saturated saline solution, and then dried over sodiumsulfate. The solvent was distilled off and the residue wasrecrystallized from ethanol to give 11.5 g of 2,3-diallyloxyfluorenoneas a yellow needle-like crystal.

Melting point: 112.0-113.0° C.

By using a suitable starting material, compounds of the Examples 55, 57,67, 70 to 73, 75 to 77, 88, 90, 92 to 95, 98, 102, 103, 104 and 148 to150 were obtained according to the same manner as that described inExample 4.

EXAMPLE 5

2,3-Diallyloxyfluorenone (11.5 g) was added to tetralin (100 ml) and themixture was heated at reflux for 2 hours. After cooling, the reactionsolution was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate (9:1)) and recrystallized from toluene to give5.5 g of 1,4-diallyl-2,3-dihydroxyfluorenone as a red needle-likecrystal.

Melting point: 153.0-154.0° C.

By using a suitable starting material, compounds of the Examples 9 to12, 14 to 19, 22, 27 to 37, 41 to 45, 47 to 62, 64, 68 and 91 wereobtained according to the same manner as that described in Example 5.

EXAMPLE 6

To ethanol (30 ml), 1,4-diallyl-2,3-dihydroxyfluorenone (1.0 g) and 5%palladium-carbon (0.1 g) were added, and the mixture was catalyticallyreduced at normal temperature, at normal pressure. After the catalystwas removed, the reaction product was concentrated and recrystallizedfrom water-containing ethanol to give 0.5 g of1,4-di-n-propyl-2,3-dihydroxyfluorenone as a red needle-like crystal.

Melting point: 193.0-194.0° C.

By using a suitable starting material, compounds of the Examples 12, 32,36 to 39, 51 to 54, 109, 110, 114, 117, 122, 124, 126 to 134, 139, 143,145 to 147 and 153 were obtained according to the same manner as thatdescribed in Example 6

EXAMPLE 7

1,5-Di-n-propyl-2,7-dihydroxyfluorenone (0.5 g) was suspended in aceticacid (5 ml), to which was added sulfuryl chloride (1.0 ml) and themixture was stirred at room temperature for 15 hours. Water (20 ml) wasadded to the reaction solution and the resulting precipitate wasfiltered. The precipitate was washed with water, dried and then purifiedby silica gel column chromatography (eluent: dichloromethane). It wasrecrystallized from chloroform-n-hexane to give 0.3 g of3,8-dichloro-1,6-di-n-propyl-2,7-dihydroxyfluorenone as an orangepowder.

Melting point: 134.5-135.5° C.

By using a suitable starting material, compounds of the Examples 33, 34,65, 89 to 92, 113 and 148 to 150 were obtained according to the samemanner as that described in Example 7.

EXAMPLE 8

1,6-Diallyl-2,7-dihydroxyfluorenone (1.0 g) was dissolved in pyridine(10 ml), to which was added acetic anhydride (1.0 ml) and the mixturewas stirred at room temperature for 15 minutes. Water (200 ml) was addedto the reaction solution and the resulting precipitate was filtered. Theprecipitate was washed with water, dried and then purified by silica gelcolumn chromatography (eluent: dichloromethane). It was recrystallizedfrom dichloromethane-n-hexane to give 1.2 g of1,6-diallyl-2,7-diacetoxyfluorenone as a yellow needle-like crystal.

Melting point: 170.0-172.0° C.

By using a suitable starting material, compounds of the Examples 107,108, 111 and 134 were obtained according to the same manner as thatdescribed in Example 8.

By using a suitable starting material, compounds shown in the Table 4were obtained according to the same manner as that described in Example1.

                                      TABLE 4                                     __________________________________________________________________________    1 #STR35##                                                                                             Shape of crystals                                                                            Melting point                         Example                                                                            (R.sup.1).sub.p                                                                        (R.sup.2).sub.q                                                                          (Solvent for recrystallization)                                                              (° C.)                         __________________________________________________________________________     9   1-OH     H          yellow prism-like crystals                                                                   90.9-92.0                                  2-CH.sub.2 CH═CH.sub.2                                                                        (ethanol)                                            10   1-OH     H          yellow prism-like crystals                                                                   41.0-42.0                                  4-CH.sub.2 CH═CH.sub.2                                                                        (n-hexane)                                           11   1-OH     H          yellow powdered                                                                              92.0-96.0                                  2-CH.sub.2 CH═CH.sub.2                                                                        (n-hexane)                                                4-CH.sub.3                                                               12   1-OH     H          yellow powdered                                                                              109.0-111.0                                2-CH.sub.2 CH.sub.2 CH.sub.3                                                                      (n-hexane)                                                4-CH.sub.3                                                               13   1-OH     7-OH       yellow powdered                                                                              193.0-194.0                           14   1-OH     6-CH.sub.2 CH═CH.sub.2                                                               orange powdered                                                                              165.0-167.0                                2-CH.sub.2 CH═CH.sub.2                                                             7-OH       (chloroform-n-hexane)                                15   1-OH     6-CH.sub.2 CH═CH.sub.2                                                               orange powdered                                                                              176.0-177.0                                4-CH.sub.2 CH═CH.sub.2                                                             7-OH       (chloroform-n-hexane)                                16   1-OH     6-CH.sub.2 CH═CH.sub.2                                                               yellow powdered                                                                              83.0-86.0                                  2-CH.sub.2 CH═CH.sub.2                                                             7-OH       (n-hexane)                                                4-CH.sub.2 CH═CH.sub.2                                                             8-CH.sub.2 CH═CH.sub.2                                      17   1-CH.sub.2 CH═CH.sub.2                                                             H          orange needle-like crystals                                                                  166.0-168.0                                2-OH                (chloroform-n-hexane)                                18   2-OH     H          orange needle-like crystals                                                                  153.0-154.0                                3-CH.sub.2 CH═CH.sub.2                                                                        (chloroform-n-hexane)                                19   1-CH.sub.2 CH═CH.sub.2                                                             H          orange needle-like crystals                                                                  138.0-141.0                                2-OH                (n-hexane)                                                3-CH.sub.2 CH═CH.sub.2                                               20   2-OH     H          Yellow powdered                                                                              247.0-248.0                                3-OH                (ethyl acetate)                                      21   1-CH.sub.2 CH═CH                                                                   H          red needle-like crystals                                                                     153.0-154.0                                2-OH                (toluene)                                                 3-OH                                                                          4-CH.sub.2 CH═CH.sub.2                                               22   1-CH.sub.2 CH.sub.2 CH.sub.3                                                           H          red needle-like crystals                                                                     193.0-194.0                                2-OH                (water-containing ethanol)                                3-OH                                                                          4-CH.sub.2 CH.sub.2 CH.sub.3                                             23   2-OH     5-OH       red needle-like crystals                                                                     more than 300                              3-OH                (water-containing ethanol)                           24   2-OH     7-OH       dark orange needle-like crystals                                                             more than 300                              3-OH                (water-containing ethanol)                           25   2-OH     6-OH       claret powdered                                                                              more than 300                              3-OH     7-OH       (water-containing ethanol)                           26   2-OH     5-OH       red powdered   more than 300                                                  (ethanol)                                            27   1-CH.sub.2 CH═CH.sub.2                                                             5-OH       orange powdered                                                                              182.0-185.0                                2-OH     6-CH.sub.2 CH═CH.sub.2                                                               (diethyl ether-n-hexane)                             28   1-CH.sub.2 CH═CH.sub.2                                                             5-OH       orange powdered                                                                              160.0-164.0                                2-OH     8-CH.sub.2 CH═CH.sub.2                                                               (diethyl ether-n-hexane)                             29   2-OH     5-OH       violet powdered                                                                              183.0-185.0                                3-CH.sub.2 CH═CH.sub.2                                                             6-CH.sub.2 CH═CH.sub.2                                                               (chloroform-diethyl ether)                           30   2-OH     5-OH       orange powdered                                                                              193.0-196.0                                3-CH.sub.2 CH═CH.sub.2                                                             8-CH.sub.2 CH═CH.sub.2                                                               (chloroform-diethyl ether)                           31   1-CH.sub.2 CH═CH.sub.2                                                             5-OH       red powdered   91.0-93.0                                  2-OH     6-CH.sub.2 CH═CH.sub.2                                                               (diethyl ether-n-hexane)                                  3-CH.sub.2 CH═CH.sub.2                                                             8-CH.sub.2 CH═CH.sub.2                                      32   1-CH.sub.2 CH.sub.2 CH.sub.3                                                           5-OH       red prism-like crystals                                                                       113.0-114.0*                              2-OH     6-CH.sub.2 CH.sub.2 CH.sub.3                                                             (n-hexane)                                                3-CH.sub.2 CH.sub.2 CH.sub.3                                                           8-CH.sub.2 CH.sub.2 CH.sub.3                                    33   1-CH.sub.2 CH═CH.sub.2                                                             5-OH       orange powdered                                                                              154.0-156.0                                2-OH     6-CH.sub.2 CH═CH.sub.2                                                               (chloroform-n-hexane)                                     3-Cl     8-Cl                                                            34   1-CH.sub.2 CH═CH.sub.2                                                             5-OH       orange powdered                                                                              158.0-160.0                                2-OH     6-Cl       (chloroform-n-hexane)                                     3-Cl     8-CH.sub.2 CH═CH.sub.2                                      35   2-OH     5-OH       red needle-like crystals                                                                     235.0-237.0                                3-CH.sub.2 CH.sub.2 ═CH.sub.2                                                                 (chloroform-methanol)                                36   2-OH     5-OCH.sub.3                                                                              red powdered   214.0-217.0                                3-CH(CH.sub.3).sub.2                                                                              (ethyl acetate-n-hexane)                             37   2-OH     5-OCH.sub.3                                                                              orange powdered                                                                              243.0-245.0                                3-CH(CH.sub.3).sub.2                                                                   7-CH(CH.sub.3).sub.2                                                                     (n-hexane)                                           38                                                                                 2 #STR36##                                                                             5-OCH.sub.3                                                                              red powdered (ethyl acetate-n-hexane)                                                        192.0-194.0                           39                                                                                 3 #STR37##                                                                             4 #STR38## red powdered (ethyl acetate-n-hexane)                                                        224.0-226.0                           40   2-OH     6-OH       dark orange powdered                                                                         268.0-271.0                                                    (ethyl acetate)                                      41   1-CH.sub.2 CH═CH.sub.2                                                             5-CH.sub.2 CH═CH.sub.2                                                               yellow powdered                                                                              201.0-204.0                                2-OH     6-OH       (chloroform-diethyl                                                           ether-n-hexane)                                      42   1-CH.sub.2 CH═CH.sub.2                                                             6-OH       orange powdered                                                                              206.0-209.0                                2-OH     7-CH.sub.2 CH═CH.sub.2                                                               (ethyl acetate-n-hexane)                             43   2-OH     5-CH.sub.2 CH═CH.sub.2                                                               orange powdered                                                                              230.0-233.0                                3-CH.sub.2 CH═CH.sub.2                                                             6-OH       (chloroform-diethyl                                                           ether n-hexane)                                      44   2-OH     6-OH       orange powdered                                                                              225.0-228.0                                3-CH.sub.2 CH═CH.sub.2                                                             7-CH.sub.2 CH═CH.sub.2                                                               (chloroform-methanol)                                45   1-CH.sub.2 CH═CH.sub.2                                                             5-CH.sub.2 CH═CH.sub.2                                                               yellow powdered                                                                              143.0-145.0                                2-OH     6-OH       (n-hexane)                                                3-CH.sub.2 CH═CH.sub.2                                                             7-CH.sub.2 CH═CH.sub.2                                      46   2-OH     7-OH       violet powdered                                                                              more than 300                                                  (ethyl acetate)                                      47   1-CH.sub.2 CH═CH.sub.2                                                             6-CH.sub.2 CH═CH.sub.2                                                               orange powdered                                                                              185.0-188.0                                2-OH     7-OH       (ethyl acetate-n-hexane)                             48   1-CH.sub.2 CH═CH.sub.2                                                             7-OH       red powdered   143.0-145.0                                2-OH     8-CH.sub.2 CH═CH.sub.2                                                               (chloroform)                                         49   2-OH     6-CH.sub.2 CH═CH.sub.2                                                               beige powdered 189.0-193.0                                3-CH.sub.2 CH═CH.sub.2                                                             7-OH       (ethyl acetate-n-hexane)                             50   1-CH.sub.2 CH═CH.sub.2                                                             6-CH.sub.2 CH═CH.sub.2                                                               red needle-like crystals                                                                     90.0-91.0                                  2-OH     7-OH       (n-hexane)                                                3-CH.sub.2 CH═CH.sub.2                                                             8-CH.sub.2 CH═CH.sub.2                                      51   1-CH.sub.2 CH.sub.2 CH.sub.3                                                           6-CH.sub.2 CH.sub.2 CH.sub.3                                                             reddish orange needle-like crystals                                                          192.0-193.0                                2-OH     7-OH       (water-containing ethanol)                           52   2-OH     6-CH.sub.2 CH.sub.2 CH.sub.3                                                             orange needle-like crystals                                                                  213.0-214.0                                3-CH.sub.2 CH.sub.2 CH.sub.3                                                           7-OH       (water-containing ethanol)                           53   1-CH.sub.2 CH.sub.2 CH.sub.3                                                           6-CH.sub.2 CH.sub.2 CH.sub.3                                                             yellow needle-like crystals                                                                  88.0-89.0                                  2-OH     7-OH       (n-hexane)                                                3-CH.sub.2 CH.sub.2 CH.sub.3                                                           8-CH.sub.2 CH.sub.2 CH.sub.3                                    54   1-CH.sub.2 CH.sub.2 CH.sub.3                                                           6-CH.sub.2 CH.sub.2 CH.sub.3                                                             orange powdered                                                                              134.5-135.5                                2-OH     7-OH       (chloroform-n-hexane)                                     3-Cl     8-Cl                                                            55   1-CH.sub.2 CH═CH.sub.2                                                             6-CH.sub.2 CH═CH.sub.2                                                               orange needle-like crystals                                                                  164.0-165.0                                2-OH     7-OCH.sub.2 CH═CH.sub.2                                                              (chloroform-n-hexane)                                     3-CH.sub.2 CH═CH.sub.2                                               56   1-CH.sub.2 CH═CH.sub.2                                                             6-CH.sub.2 CH═CH.sub.2                                                               dark orange prism-like crystals                                                              143.0-145.0                                2-OH     7-OH       (toluene)                                                 3-OH                                                                          4-CH.sub.2 CH═CH.sub.2                                               57   1-CH.sub.2 CH═CH.sub.2                                                             7-OCH.sub.2 CH.sub.2 ═CH.sub.2                                                       orange powdered                                                                              165.0-167.0                                2-OH                (chloroform-n-hexane)                                     3-OH                                                                          4-CH.sub.2 CH═CH.sub.2                                               58   2-CH.sub.2 CH═CH.sub.2                                                             H          orange powdered                                                                              176.0-177.0                                3-OH                (chloroform)                                         59   3-OH     H          orange powdered                                                                              205.0-207.0                                4-CH.sub.2 CH═CH.sub.2                                                                        (chloroform)                                         60   2-CH.sub.2 CH═CH.sub.2                                                             H          yellow powdered                                                                              184.0-185.0                                3-OH                (ethyl acetate-n-hexane)                                  4-CH.sub.2 CH═CH.sub.2                                               61   1-CH.sub.2 CH═CH.sub.2                                                             H          yellow powdered                                                                              213.0-216.0                                4-OH                (chloroform-n-hexane)                                62   3-CH.sub.2 CH═CH.sub.2                                                             H          orange powdered                                                                              173.0-174.0                                4-OH                (chloroform-n-hexane)                                63   1-SCH.sub.3                                                                            H          orange powdered                                                                              262.0-265.0                                4-OH                (chloroform-methanol)                                64   1-SCH.sub.3                                                                            H          yellow powdered                                                                              196.0-198.0                                3-CH.sub.2 CH═CH.sub.2                                                                        (chloroform-n-hexane)                                     4-OH                                                                     65   H        5-CH.sub.3 reddish orange oily                                                                          --                                                  7-Br                                                                          8-OH                                                            66   H        5-CH.sub.3 yellow needle-like crystals                                                                  121.0-123.0                                         8-OCH.sub.3                                                                              (ethanol)                                            67   H        5-CH.sub.3 yellow prism-like crystals                                                                    99.0-101.0                                         8-OCH.sub.2 CH═CH--CH.sub.3                                                          (ethanol)                                            68   H                                                                                      5 #STR39## yellow powdered (n-hexane-ethanol)                                                           76.0-78.0                                           8-OH                                                            69   H        5-CH.sub.3 yellow needle-like crystals                                                                  124.0-125.0                                         8-OH       (ethanol)                                            70   1-OCH.sub.2 CH═CH.sub.2                                                            H          yellow oily    --                                    71   3-OCH.sub.2 CH═CH.sub.2                                                            H          yellow needle-like crystals                                                                  81.0-83.0                                                      (ethanol)                                            72   4-OCH.sub.2 CH═CH.sub.2                                                            H          yellow needle-like crystals                                                                  112.0-114.0                                                    (ethanol)                                            73   2-OCH.sub.2 CH═CH.sub.2                                                            H          yellow plate crystals                                                                        79.0-81.0                                                      (ethanol)                                            74   2-OCH.sub.3                                                                            5-OCH.sub.3                                                                              orange needle-like crystals                                                                  131.0-133.0                                                    (n-hexane)                                           75   H        5-CH.sub.3 orange oily                                                        8-OCH.sub.2 CH═CH.sub.2                                     76   2-OCH.sub.2 CH═CH.sub.2                                                            5-OCH.sub.2 CH═CH.sub.2                                                              red oily                                                  3-CH.sub.2 CH═CH.sub.2                                                             6-CH.sub.2 CH═CH.sub.2                                      77   1-OCH.sub.2 CH═CH.sub.2                                                            7-OCH.sub.2 CH═CH.sub.2                                                              yellow needle-like crystals                                                                  79.0-80.0                                                      (ethanol)                                            78   1-OCH.sub.3                                                                            7-OCH.sub.3                                                                              yellow powdered                                                                              124.0-126.0                                                    (ethanol)                                            79   2-OCH.sub.2 CH═CH.sub.2                                                            H          yellow needle-like crystals                                                                  112.0-113.0                                3-OCH.sub.2 CH═CH.sub.2                                                                       (ethanol)                                            80   2-OCH.sub.3                                                                            H          yellow scaly crystals                                                                        162.0-164.0                                3-OCH.sub.3         (ethanol)                                            81   2-OH     5-OCH.sub.3                                                                              red powdered   210.0-212.0                                                    (chloroform-diethyl ether)                           82   1-OCH.sub.3                                                                            H          yellow prism-like crystals                                                                   144.0-145.0                                                    (n-hexane-ethyl acetate)                             83   3-OCH.sub.3                                                                            H          yellow needle-like crystals                                                                   99.0-100.0                                                    (n-hexane-ethyl acetate)                             84   1-SCH.sub.3                                                                            H          orange powdered                                                                              180.0-183.0                                4-OCH.sub.3         (n-hexane-ethyl acetate)                             85   2-OCH.sub.3                                                                            7-OCH.sub.3                                                                              red needle-like crystals                                                                     123.0-124.0                                                    (ethanol)                                            86   2-OH     7-OCH.sub.3                                                                              violet powdered                                                                              188.0-192.0                                                    (chloroform)                                         87   2-OCH.sub.3                                                                            6-OCH.sub.3                                                                              yellow needle-like crystals                                                                  126.0-128.0                                                    (ethanol)                                            88   2-OCH.sub.2 CH═CH.sub.2                                                            5-OCH.sub.2 CH═CH.sub.2                                                              orange needle-like crystals                                                                  75.0-76.0                                                      (ethanol)                                            89   2-OH     7-Br       reddish orange oily                                                                          --                                    90   2-OCH.sub.2 CH═CH.sub.2                                                            7-Br       yellow powdered                                                                              123.0-124.0                                                    (ethanol)                                            91   2-OH     7-Br       red powdered   --                                         3-CH.sub.2 CH═CH.sub.2                                               92   1-CH.sub.2 CH═CH.sub.2                                                             7-Br       yellow powdered                                                                              83.0-84.0                                  2-OCH.sub.2 CH═CH.sub.2                                                                       (ethyl acetate-n-hexane)                             93   2-OCH.sub.2 CH═CH.sub.2                                                            6-OCH.sub.2 CH═CH.sub.2                                                              yellow needle-like crystals                                                                  79.0-80.0                                                      (ethanol)                                            94   2-OCH.sub.2 CH═CH.sub.2                                                            7-OCH.sub.2 CH═CH.sub.2                                                              orange needle-like crystals                                                                  89.0-90.0                                                      (ethanol)                                            95   1-SCH.sub.3                                                                            H          yellow powdered                                                                              126.0-127.0                                4-OCH.sub.2 CH═CH.sub.2                                                                       (n-hexane-ethyl acetate)                             96   2-OCH.sub.3                                                                            H          yellow needle-like crystals                                                                  75.0-76.0                                                      (ethyl acetate-n-hexane)                             97   H        5-CH.sub.3 reddish orange oily                                                                          --                                                  7-CH.sub.3                                                                    8-OCH.sub.3                                                     98   2-OCH.sub.2 CH═CH.sub.2                                                            6-CH.sub.2 CH═CH.sub.2                                                               orange needle-like crystals                                                                  103.0-105.0                                3-CH.sub.2 CH═CH.sub.2                                                             7-OCH.sub.2 CH═CH.sub.2                                                              (ethyl acetate-n-hexane)                             99   2-OCH.sub.3                                                                            6-OCH.sub.3                                                                              orange needle-like crystals                                                                  194.0-195.0                                3-OCH.sub.3                                                                            7-OCH.sub.3                                                                              (ethyl acetate-n-hexane)                             100  2-OCH.sub.3                                                                            5-OCH.sub.3                                                                              orange needle-like crystals                                                                  184.0-186.0                                3-OCH.sub.3         (chloroform-n-hexane)                                101  2-OCH.sub.3                                                                            7-OCH.sub.3                                                                              orange needle-like crystals                                                                  164.0-165.0                                3-OCH.sub.3         (chloroform-n-hexane)                                102  2-OCH.sub.2 CH═CH.sub.2                                                            5-OCH.sub.2 CH═CH.sub.2                                                              orange needle-like crystals                                                                  77.0-79.0                                  3-OCH.sub.2 CH═CH.sub.2                                                                       (n-hexane)                                           103  2-OCH.sub.2 CH═CH.sub.2                                                            6-OCH.sub.2 CH═CH.sub.2                                                              orange needle-like crystals                                                                   99.0-100.0                                3-OCH.sub.2 CH═CH.sub.2                                                            7-OCH.sub.2 CH═CH.sub.2                                                              (chloroform-n-hexane)                                104  2-OCH.sub.2 CH═CH.sub.2                                                            7-OCH.sub.2 CH═CH.sub.2                                                              orange powdered                                                                              116.0-117.0                                3-OCH.sub.2 CH═CH.sub.2                                                                       (chloroform-n-hexane)                                105  2-OH     5-OCH.sub.3                                                                              red powdered   210.0-212.0                                                    (chloroform-diethyl ether)                           106                                                                                6 #STR40##                                                                             7 #STR41## yellow needle-like crystals (dichloromethane-n-he                             xane)          170.0-172.0                           107                                                                                8 #STR42##                                                                             9 #STR43## yellow needle-like crystals (dichloromethane-n-he                             xane)          155.0-156.0                           108                                                                                0 #STR44##                                                                             1 #STR45## yellow needle-like crystals (ethyl                                            acetate-n-hexane)                                                                            137.0-138.0                           __________________________________________________________________________     *When repeating recrystallization, 116.5-117.0° C.                

COMPOUND OF EXAMPLE 65

¹ H-NMR (CDCl₃, δ ppm); 2.44 (3H, s), 7.35 (1H, s), 7.43-7.70 (4H, m),9.00 (1H, s).

COMPOUND OF EXAMPLE 70

¹ H-NMR (CDCl₃, δ ppm); 4.73-4.83 (2H, m), 5.31-5.36 (1H, m), 5.51-5.59(1H, m), 7.29 (1H, ddd, J=1.5 Hz, J=7 Hz, J=7 Hz), 7.37-7.51 (3H, m),7.64 (1H, d, J=7.5 Hz).

COMPOUND OF EXAMPLE 75

¹ H-NMR (CDCl₃, δ ppm); 2.53 (3H, s), 4.72 (2H, dd, J=1.5 Hz, J=3 Hz),4.70-4.77 (2H, m), 5.28-5.37 (1H, m), 5.50-5.60 (1H, m), 6.01-6.18 (1H,m), 6.73 (1H, d, J=8.5 Hz), 7.18 (1H, d, J=8.5 Hz), 7.30 (1H, d, J=7.5Hz), 7.46 (1H, dd, J=7.5 Hz, J=7.5 Hz), 7.62 (1H, d, J=7.5 Hz), 7.66(1H, dd, J=7.5 Hz, J=7.5 Hz).

COMPOUND OF EXAMPLE 76

¹ H-NMR (CDCl₃, δ ppm); 3.45 (2H, d, J=6.5 Hz), 3.93 (2H, d, J=6.5 Hz),4.90-5.50 (8H, m), 5.87-6.23 (4H, m), 6.92 (1H, s), 7.07-7.17 (1H, m),7.33-7.40 (1H, m), 7.55 (1H, s).

COMPOUND OF EXAMPLE 89

¹ H-NMR (CDCl₃, δ ppm); 6.95 (1H, dd, J=2.5 Hz, J=8 Hz), 7.11 (1H, d,J=2.5 Hz), 7.28 (1H, d, J=8 Hz), 7.35 (1H, d, J=8 Hz), 7.55 (1H, dd, J=2Hz, J=8 Hz), 7.70 (1H, d, J=2 Hz), 8.23 (1H, s).

COMPOUND OF EXAMPLE 91

¹ H-NMR (CDCl₃, δ ppm); 3.44 (2H, d, J=6.5 Hz), 5.15-5.23 (2H, m),5.92-6.07 (1H, m), 7.09-7.30 (4H, m), 7.52 (1H, dd, J=2 Hz, J=8 Hz),7.65 (1H, d, J=2 Hz).

COMPOUND OF EXAMPLE 97

¹ H-NMR (CDCl₃, δ ppm); 2.25 (3H, s), 2.30 (3H, s), 3.92 (3H, s), 7.15(1H, s), 7.41-7.68 (4H, m).

By using a suitable starting material, the following compounds wereobtained according to the same manner as that described in Example 1.

                                      TABLE 5                                     __________________________________________________________________________    1 #STR46##                                                                                                         Shape of crystals                                                                          Melting point               Example                                                                            (R.sup.1).sub.p  (R.sup.2).sub.q                                                                              (Solvent for recrystalization)                                                             (° C.)               __________________________________________________________________________    109  1-(CH.sub.2).sub.2 CH.sub.3                                                                    H              red needle-like crystals                                                                   157-158                          2-OH                            (ethanol-water)                               3-(CH.sub.2).sub.2 CH.sub.3                                              110  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OH           red powdered 158-160                          2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (ethanol-water)                          111  1-CH.sub.2 CH═ CH.sub.2                                                                    H              yellow needle-like                                                                         167-168s                         2-OCOCH.sub.3                   (ethyl acetate)                               3-OCOCH.sub.3                                                                 4-CH.sub.2 CH═ CH.sub.2                                              112  1-CH.sub.3       5-OH           red needle-like crystals                                                                   247-249                          2-OH                            (ethanol-water)                               3-CH.sub.3                                                               113  2-OH             5-OH           red powdered more than 300                    3-Br             8-Br           (ethanol-water)                          114                                                                                2 #STR47##       5-OH           red needle-like crystals (ethyl                                               acetate-n-hexane)                                                                          211-213                          2-OH                                                                          3 #STR48##                                                               115  1-CH.sub.3       5-OH           red needle-like crystals                                                                   190-191                          2-OH             6-CH.sub.2 N(CH.sub.3).sub.2                                                                 (toluene)                                     3-CH.sub.3                                                               116  1-CH.sub.3       5-OH           orange needle-like                                                                         181-182s                         2-OH             6-CH.sub.2 N(CH.sub.3).sub.2                                                                 (toluene-n-hexane)                            3-CH.sub.3       8-CH.sub.2 N(CH.sub.3).sub.2                            117                                                                                2 #STR49##       5-OH 6-CH.sub.2 N(CH.sub.3).sub.2                                                            red needle-like crystals                                                      (toluene-n-hexane)                                                                         198-200                          2-OH                                                                          3 #STR50##                                                               118  1-CH.sub.3       5-OH           orange needle-like                                                                         254-256s                         2-OH             6-CH.sub.3     (acetonitrile)                                3-CH.sub.3                                                               119  1-CH.sub.3       5-OH           orange needle-like                                                                         more than 300                    2-OH             6-CH.sub.3     (acetonitrile)                                3-CH.sub.3       8-CH.sub.3                                              120  1-CH.sub.3       5-OH           brown needle-like crystals                                                                 285-287                          2-OH 3-CH.sub.3                                                                                4 #STR51##     (dichloromethane-methanol)               121  1-CH.sub.3       5-OH           red powdered 138-139                          2-OH             6-CH.sub.2 NHCH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                               (toluene-n-hexane)                            3-CH.sub.3                                                               122  1-(CH).sub.2 CH.sub.3                                                                          5-OH           red needle-like crystals                                                                   208-213                          2-OH             6-(CH).sub.2 CH.sub.3                                                                        (toluene)                                     3-CH.sub.2 N(CH.sub.3).sub.2                                             123  1-CH.sub.3       5-OH           orange powdered                                                                            278-280                          2-OH 3-CH.sub.3                                                                                5 #STR52##     (ethyl acetate)                          124  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OH           red needle crystals                                                                        129-130                          2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (toluene-n-hexane)                            3-CH.sub.2 NHCH.sub.2 CO.sub.2 C.sub.2 H.sub.5                           125  1-CH.sub.3       5-OH           red needle-like crystals                                                                   178-179                          2-OH             6-CH.sub.2 OCH.sub.3                                                                         (toluene-n-hexane)                            3-CH.sub.3                                                               126  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OH           red needle crystals                                                                        250-252                          2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (ethanol-water)                               6 #STR53##                                                               127  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OH           orange powdered                                                                            239-241                          2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (acetonitrile)                                7 #STR54##                                                               128                                                                                2 #STR55##                                                                                     8 #STR56##     red powdered (toluene)                                                                     236-237                          2-OH                                                                          3 #STR57##                                                               129  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OH           orange needle-like                                                                         194-195s                         2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (toluene-n-hexane)                            3-CH.sub.2 OCH.sub.3                                                     130  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OH           red needle-like crystals                                                                   204-205                          2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (acetonitrile)                                9 #STR58##                                                               131  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OH           red sacley crystals                                                                        145-146                          2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (isopropyl ether)                             0 #STR59##                                                               132  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OH           red needle crystals                                                                        123-124                          2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (toluene-n-hexane)                            1 #STR60##                                                               133  1-CH.sub.3       5-OH           orange powdered                                                                            262-264                          2-OH 3-CH.sub.3                                                                                2 #STR61##     (dimethylformamide-water)                134  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OCOCH.sub.3  yellow needle crystals                                                                     142-143                          2-OCOCH.sub.3    6-(CH.sub.2).sub.2 CH.sub.3                                                                  (acetonitrile)                                3-(CH.sub.2).sub.2 CH.sub.3                                                                    8-(CH.sub.2).sub.2 CH.sub.3                             135  1-CH.sub.3       5-OH           orange powdered                                                                            219.5-221.0                      2-OH 3-CH.sub.3                                                                                3 #STR62##     (toluene)                                136  1-CH.sub.3       5-OH           orange needle-like                                                                           205-206.5                      2-OH 3-CH.sub.3                                                                                4 #STR63##     (toluene)                                137  1-CH.sub.3       5-OH           red powdered 252.5-255.5                      2-OH 3-CH.sub.3                                                                                5 #STR64##     (dichloromethane-n-hexane)               138  1-CH.sub.3       5-OH           brown powdered                                                                               278-279.5                      2-OH 3-CH.sub.3                                                                                6 #STR65##     (toluene-n-hexane)                       139                                                                                2 #STR66##       5-OH           orange powdered                                                                            157.8-159                        2-OH             6-CH.sub.2 N(CH.sub.3).sub.2                                                                 (toluene-n-hexane)                            3 #STR67##       8-CH.sub.2 N(CH.sub.3).sub.2                            140  1-CH.sub.3       5-OH           brown needle-like crystals                                                                 288.5-290.5                      2-OH             6-CHO          (dichloromethane-acetone)                     3-CH.sub.3                                                               141  1-CH.sub.3       5-OH           orange needle-like                                                                         200-201s                         2-OH 3-CH.sub.3                                                                                7 #STR68##     (acetonitrile)                           142  1-CH.sub.3       5-OH           orange powdered                                                                            165.5-167                        2-OH 3-CH.sub.3                                                                                8 #STR69##     (toluene-n-hexane)                       143                                                                                9 #STR70##       5-OH           yellow needle-like                                                                         136.5-137                        2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (toluene-n-hexane)                            3-(CH.sub.2).sub.2 CH.sub.3                                                                    8-(CH.sub.2).sub.2 CH.sub.3                             144  1-CH.sub.3       5-OH           orange needle crystals                                                                     254.5-255.5                      2-OH             6-CH.sub.2 CN  (acetonitrile)                                3-CH.sub.3                                                               145  2-OH             5-OH           Brown needle-like crystals                                                                 194.6-195.8                      3-(CH.sub.2).sub.2 CH.sub.3                                                                    6-(CH.sub.2).sub.2 CH.sub.3                                                                  (toluene)                                                      8-(CH.sub.2).sub.2 CH.sub.3                             146  1-(CH.sub.2).sub.2 CH.sub.3                                                                    5-OH           Orange needle-like                                                                         203.4-204.8                      2-OH             6-(CH.sub.2).sub.2 CH.sub.3                                                                  (toluene-n-hexane)                            3-(CH.sub.2).sub.2 CH.sub.3                                              148  1-Cl             5-OCH.sub.2 CH.sub.2 ═ CH.sub.2                                                          yellow needle-like                                                                         132-134s                         2-OCH.sub.2 CH.sub.2 ═ CH.sub.2                                                            8-Cl           (dichloromethane-n-hexane)                    3-Cl                                                                     149  2-OCH.sub.2 CH.sub.2 ═ CH.sub.2                                                            5-OCH.sub.2 CH.sub.2 ═ CH.sub.2                                                          yellow needle-like                                                                         117-118s                         3-Cl             6-Cl           (dichloromethane-n-hexane)               150  2-OCH.sub.2 CH.sub.2 ═ CH.sub.2                                                            5-OCH.sub.2 CH═ CH.sub.2                                                                 yellow needle-like                                                                         158-160s                         3-Cl             8-Cl           (dichloromethanbe-n-hexane)              151  1-CH.sub.3       5-OCH.sub.3    orange partciculate                                                                        100-102s                         2-OCH.sub.3                     (n-hexane)                                    3-CH.sub.3                                                               152  1-CH.sub.3       5-OH           orange powdered                                                                            228.5-229.5                      2-OH             6-CH.sub.2 N.sup.+ (CH.sub.3).sub.3                                                          (nitromethane-diethyl                                                                      (I.sup.-)                        3-CH.sub.3                                                               153                                                                                2 #STR71##       5-OCH.sub.3    yellow powdered                                                                            122.5-124                        2-OCH.sub.3                     (ethyl acetate-n-hexane)                      3 #STR72##                                                               __________________________________________________________________________

EXAMPLE 154

To ethanol (90 ml), a 50% dimethylamine solution (4.5 g) andparaformaldehyde (1.5 g) were added and the mixture was stirred at 100°C. for 20 minutes. To this was added1,3-dimethyl-2,5-dihydroxyfluorenone (3.0 g), followed by stirring at100° C. for 24 minutes. After the solvent was distilled off, the residuewas purified by silica gel column chromatography (eluent: n-hexane/ethylacetate (4:1)) and recrystallized from toluene to give 2.1 g of1,3-dimethyl-6-dimethylaminomethyl-2,5-dihydroxyfluorenone as a redneedle-like crystal.

Melting point: 190.0-191.0° C.

EXAMPLE 155

To acetic acid (30 ml), a 50% dimethylamine solution (1.5 g) andparaformaldehyde (0.5 g) were added and the mixture was stirred at 120°C. for 20 minutes. To this was added 1,3-dimethyl-2,5-dihydroxyfluorenone (1.0 g), followed by stirring at 120° C. for 8hours. The reaction solution was neutralized with an aqueous 20% sodiumhydroxide solution and extracted with dichloromethane, then the extractwas dried over magnesium sulfate. The solvent was distilled off and theresidue was recrystallized from toluene-n-hexane to give 750 mg of1,3-dimethyl-6,8-bisdimethylaminomethyl-2,5-dihydroxyfluorenone as anorange needle-like crystal.

Melting point: 181.0-182.0° C.

By using a suitable starting material, compounds of the above Examples117, 122 and 139 were obtained according to the same manner as thatdescribed in Examples 155 and 156.

EXAMPLE 156

To ethanol (20 ml), 6-dimethylaminomethyl-2,5-dihydroxyfluorenone (200mg), 10% palladium-carbon (10 mg) and ammonium formate (212 mg) wereadded and the mixture was stirred at 90° C. for 10 minutes. After thecatalyst was removed, the reaction solution was concentrated andrecrystallized from acetonitrile to give 156 mg of1,3,6-trimethyl-2,5-dihydroxyfluorenone as an orange needle-likecrystal.

Melting point: 254.0-256.0° C.

By using a suitable starting material, compounds of the above Examples11, 12, 65 to 69, 75, 97, 112, 115, 116, 119 to 121, 123, 125, 133, 135to 138, 140 to 142, 144, 151 and 152 were obtained according to the samemanner as that described in Examples 156.

EXAMPLE 157

To a mixed liquid of acetonitrile (100 ml) and dimethylformamide (20ml), 3-dimethyl-6-trimethylammoniummethyl-2,5-dihydroxyfluorenone iodide(550 mg) and imidazole (427 mg) were added and the mixture was stirredat 90° C. for 30 minutes. After the solvent was distilled off, theresidue was purified by silica gel column chromatography (eluent:dichloromethane/methanol (20:1)) and recrystallized fromdichloromethane-methanol to give 217 mg of1,3-dimethyl-6-(1-imidazolylmethyl-2, 5-dihydroxyfluorenone as a brownpowder.

Melting point: 285.0-287.0° C.

EXAMPLE 158

1,3-Dimethyl-6-trimethylammoniummethyl-2,5-dihydroxyfluorenone iodide(420 mg) was added to methanol (42 ml) and the mixture was stirred at90° C. for 24 hours. After the solvent was distilled off, the residuewas purified by silica gel column chromatography (eluent: n-hexane/ethylacetate (4:1)) and recrystallized from toluene-n-hexane to give 100 mgof 1,3-dimethyl-6-methoxymethyl-2,5-dihydroxyfluorenone as a redneedle-like crystal.

Melting point: 178.0-179.0° C.

EXAMPLE 159

To a mixed liquid of acetonitrile (60 ml) and dimethylformamide (9 ml),hydrochloric acid glycine ethyl ester (477 mg) and potassium carbonate(472 mg) were added and the mixture was stirred at 90° C. for one hour.To this was added1,3-dimethyl-6-trimethylammoniummethyl-2,5-dihydroxyfluorenone iodide(300 mg), followed by stirring at 90° C. for one hour. After the solventwas distilled off, ethyl acetate was added to the residue and potassiumcarbonate was filtered. After the solvent was distilled off, the residuewas purified by silica gel column chromatography (eluent: n-hexane/ethylacetate (3:1)) and recrystallized from toluene-n-hexane to give 150 mgof1,3-dimethyl-6-ethoxycarboxylmethylaminomethyl-2,5-dihydroxyfluorenoneas a red powder.

Melting point: 138.0-139.0° C.

By using a suitable starting material, compounds of the above Examples115 to 117, 122, 123, 124, 126 to 133 and 139 were obtained according tothe same manner as that described in Examples 157 to 159.

EXAMPLE 160

To dimethylformamide (2 ml),1,3-dimethyl-6-dimethylaminomethyl-2,5-dihydroxyfluorenone (150 mg) and2-mercaptopyridine (168 mg) were added and the mixture was stirred at150° C. for 3.5 hours. After the solvent was distilled off, the residuewas purified by silica gel column chromatography (eluent: n-hexane/ethylacetate (5:1)) and recrystallized from toluene to give 90 mg of1,3-dimethyl-6-(2-pyridylthio)methyl-2,5-dihydroxyfluorenone as anorange powder.

Melting point: 219.6-221° C.

By using a suitable starting material, compounds of the above Examples136 to 138, 141 and 142 were obtained according to the same manner asthat described in Example 160.

Pharmacological test 1

Nerve cells of the cerebral cortex were removed aseptically from a fetalrat (17 days-old) and cultured according to a Asou's method Asou, H.Brain Res., 332; pages 355-357 (1985)!. After the meninx, blood vessel,etc. were removed from the cerebral hemisphere, they were put through astainless steel mesh (pore size: 140μm). Then, the isolated cells werefloated on a culture medium (Eagle's basal medium containing 10% fetalbovine serum and glucose of 1 g/l) and 1.5×10⁶ cells were respectivelyseeded on a dish (diameter: 35 mm) coated with poly-L-lysine to initiatethe culture (37° C., 3% CO₂). After 24 hours, the culture medium wasreplaced by a culture medium containing a test compound and cultured foradditional 9 days.

10 Days after initiation of the culture, neurite sprouting (NS) wasevaluated under phase contrast microscopy by comparing with the controlgroup. The results are shown in Table 6 below.

(++): extremely strong in comparison with the control

(+): strong in comparison with the control

(±): same as the control

(-): inferior to the control

                  TABLE 6                                                         ______________________________________                                        Test Compound      Dose (mole) Culture                                        ______________________________________                                        Compound of Example 11                                                                           10.sup.-5   NS (+)                                         Compound of Example 14                                                                           10.sup.-7   NS (++)                                        Compound of Example 16                                                                           10.sup.-7   NS (+)                                         Compound of Example 17                                                                           10.sup.-5   NS (++)                                        Compound of Example 18                                                                           10.sup.-5   NS (++)                                        Compound of Example 19                                                                           10.sup.-5   NS (++)                                        Compound of Example 21                                                                           10.sup.-7   NS (++)                                        Compound of Example 26                                                                           10.sup.-7   NS (+)                                         Compound of Example 27                                                                           10.sup.-5   NS (+)                                         Compound of Example 28                                                                           10.sup.-5   NS (++)                                        Compound of Example 31                                                                           10.sup.-7   NS (+)                                         Compound of Example 35                                                                           10.sup.-7   NS (+)                                         Compound of Example 40                                                                           10.sup.-5   NS (++)                                        Compound of Example 45                                                                           10.sup.-7   NS (+)                                         Compound of Example 47                                                                           10.sup.-6   NS (+)                                         Compound of Example 48                                                                           10.sup.-6   NS (+)                                         Compound of Example 49                                                                           10.sup.-6   NS (+)                                         Compound of Example 60                                                                           10.sup.-7   NS (+)                                         Compound of Example 61                                                                           10.sup.-5   NS (++)                                        Compound of Example 62                                                                           10.sup.-6   NS (++)                                        0.5% Ethanol       --          NS (±)                                      ______________________________________                                    

Pharmacological Test 2

(The measurement of neurite outgrowth in primary culture of mouse dorsalroot ganglion cells)

Preparation of cells was conducted according to a method of Horie et al.H. Horie., FEBS, 296, 23 (1990)!. That is, C57BL/6 male mice aged 10 to15 weeks were used. They were bleeded to death under etheranesthetization and the backbone from cervical vertebra to sacralvertebra was removed. The capsule of dorsal root ganglion of whichventral root and dorsal root had been cut was stripped in a Ham F12medium (Flow laboratories) and then ganglia were treated with 0.25%collagenase (Worthington Biochemical Corporation) at 37° C. for 90minutes. The medium was replaced by a Hank's physiological buffersolution containing no calcium and magnesium and cells were treated with0.25% trypsin (Flow Laboratories) at room temperature for 20 minutes. Atrypsin inhibitor (Sigma, 100 μg/ml) was added to terminate the enzymereaction and trituration was conducted 20 times using a tapered Pasteurpipette. The medium was replaced again by the Ham F12 medium and cellswere put through a nylon mesh (150 μm) to remove a cell mass which hadnot been separated. Cells were suspended in the Ham F12 mediumcontaining a N1 additive Bottenstein, J. E., Exp. Cell. Res., 125, 183(1980)! (kanamycin of 60 μg/ml added).

A poly-1-lysine-coating cell disc as a culture medium which had beensubjected to 10 μg/ml laminin (Koken Cell Gen) coating treatment at 37°C. for 3 hours was placed on a 24 well dish and nerve cells (5000 to10000 cells/dish) were seeded. The test compound (concentration: 0.01mol/l) was dissolved in dimethyl sulfoxide and diluted with a phosphatebuffer solution to adjust to a final concentration, and then added to aculture solution. Cells were cultured in 5% CO₂ -95% air phase at 37° C.for 7 days.

For the measurement of neurite outgrowth, the cell disc was washed witha phosphate buffer solution 7 days after initiation of the culture andimmobilized with 4% paraformaldehyde at 4° C. for 24 hours, and thenimmune staining was conducted with Vecstatin ABC kit (Vector) using aneurofilament antibody (200 kD, manufactured by Boehringer MannheimGmbH). The periphery of the cell disc was restrictively observed undermicroscopy, and the amount of neurofilament (whole length per well) wasevaluated by comparing with the control well according to the followingcriteria: positive (+), false positive (±) and negative (-). The resultsare shown in Table 7 below.

                  TABLE 7                                                         ______________________________________                                                                   Neurite outgrowth                                  Test Compound    Dose (mole)                                                                             action                                             ______________________________________                                        Compound of Example 17                                                                         10.sup.-6 +                                                  Compound of Example 18                                                                         10.sup.-6 +                                                  Compound of Example 19                                                                         10.sup.-7 +                                                  Compound of Example 20                                                                         10.sup.-6 +                                                  Compound of Example 21                                                                         10.sup.-7 +                                                  Compound of Example 22                                                                         10.sup.-7 +                                                  Compound of Example 26                                                                         10.sup.-7 +                                                  Compound of Example 27                                                                         10.sup.-7 +                                                  Compound of Example 29                                                                         10.sup.-7 +                                                  Compound of Example 30                                                                         10.sup.-7 +                                                  Compound of Example 31                                                                         10.sup.-7 +                                                  Compound of Example 32                                                                         3 × 10.sup.-8                                                                     +                                                  Compound of Example 33                                                                         10.sup.-7 +                                                  Compound of Example 34                                                                         10.sup.-7 +                                                  Compound of Example 36                                                                         10.sup.-6 +                                                  Compound of Example 38                                                                         10.sup.-7 +                                                  Compound of Example 39                                                                         10.sup.-7 +                                                  Compound of Example 40                                                                         10.sup.-6 +                                                  Compound of Example 41                                                                         10.sup.-7 +                                                  Compound of Example 44                                                                         10.sup.-7 +                                                  Compound of Example 45                                                                         10.sup.-7 +                                                  Compaund of Example 47                                                                         10.sup.-7 +                                                  Compound of Example 48                                                                         10.sup.-7 +                                                  Compound of Example 49                                                                         10.sup.-7 +                                                  Compound of Example 50                                                                         10.sup.-7 +                                                  Compound of Example 53                                                                         10.sup.-7 +                                                  Compound of Example 54                                                                         10.sup.-7 +                                                  Compound of Example 60                                                                         10.sup.-6 +                                                  Compound of Example 62                                                                         10.sup.-6 +                                                  Compound of Example 63                                                                         10.sup.-6 +                                                  Compound of Example 64                                                                         10.sup.-6 +                                                  Compound of Example 106                                                                        10.sup.-7 +                                                  Compound of Example 108                                                                        10.sup.-7 +                                                  Compound of Example 118                                                                        3 × 10.sup.-7                                                                     +                                                  Compound of Example 123                                                                        10.sup.-7 +                                                  Compound of Example 127                                                                        10.sup.-7 +                                                  Compound of Example 131                                                                        10.sup.-7 +                                                  Compound of Example 132                                                                        10.sup.-7 +                                                  Compound of Example 134                                                                        3 × 10.sup.-8                                                                     +                                                  Compound of Example 136                                                                        3 × 10.sup.-7                                                                     +                                                  Compound of Example 141                                                                        3 × 10.sup.-8                                                                     +                                                  Compound of Example 142                                                                        3 × 10.sup.-8                                                                     +                                                  Compound of Example 143                                                                        10.sup.-7 +                                                  Compound of Example 144                                                                        10.sup.-7 +                                                  ______________________________________                                    

Pharmacological test 3

(The measurement of antioxidation action)

The antioxidation action was measured using the hyperoxidation reactionof lipid due to ascorbic acid induction Shimada, O. and Yasuda, H.BBA489, 163-172 (1977)!.

Microsome fraction was obtained from a lever of Wister rat by a Kato'smethod J. Biochem., 59, 574 (1966)!. This fraction was added to a 60 mMpotassium phosphate buffer solution (containing 45 mM potassiumchloride, 200 μM ascorbic acid and 20 μM ferrous sulfate) in an amountof 1 mg/ml and the test compound (0.1% dimethyl sulfoxide) was added,and the mixture was incubated at 37° C. for 15 minutes. The same amountof 10% trichloroacetic acid was added and the resultant was centrifuged.A portion of the supernatant was collected and the amount ofmalondialdehyde due to thiobarbituric acid (TBA value) was measuredKlaassen, C. D. and Plaa, G. L. Biochem. Pharmacol., 18: 2019 (1969)!.The inhibition ratio was calculated by the following formula:

    Inhibition ratio={1-(TBA value of specimen)/(TBA value of control)}×100,

and 50% inhibition concentration (IC₅₀) is shown in Table 8.

                  TABLE 8                                                         ______________________________________                                        Test compound      IC.sub.50  (μM)                                         ______________________________________                                        Compound of Example 21                                                                           0.1                                                        Compound of Example 27                                                                           1.6                                                        Compound of Example 31                                                                           0.2                                                        Compound of Example 47                                                                           0.2                                                        Compound of Example 49                                                                           2.1                                                        ______________________________________                                    

Pharmacological test 4

(C-GMP-PDE (type V) inhibition action)

The separation and purification of PDE from a human blood platelet wasconducted according to a method of Hidaka et al. Hidaka, H. and Asano,I., Biochem. Biophys. Acta 429, 485-497 (1976)!. That is, a bloodplatelet derived from a healthy adult was washed with water, floatedwith a Tris buffer solution and centrifuged. Then, the supernatantthereof was applied to DEAE-cellulose and separated into threefractions, FI, FII and FIII due to concentration gradient of sodiumacetate. By using FI having high affinity to C-GMP, the inhibitionaction of the test compound was examined. The influence of the drug onPDE was represented by the inhibition ratio to PDE activity in theabsence of the drug. The results are shown in Table 9.

                  TABLE 9                                                         ______________________________________                                        Test compound      IC.sub.50  (μM)                                         ______________________________________                                        Compound of Example 21                                                                           14.7                                                       Compound of Example 27                                                                           8.7                                                        Compound of Example 31                                                                           0.4                                                        Compound of Example 47                                                                           3.4                                                        Compound of Example 49                                                                           2.2                                                        ______________________________________                                    

We claim:
 1. A fluorenone derivative represented by the formula:##STR73## wherein R^(a) is a lower alkenyl group or an acetyl group;R^(b) and R^(c) are the same or different and are a hydrogen atom, alower alkenyl group, a lower alkyl group, a halogen atom, a lower alkoxygroup, a lower alkylthio group, a lower alkenyloxy group, a group of theformula: ##STR74## (wherein R⁸ and R⁹ are the same or different andindicate a hydrogen atom, a lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a pyrimidinyl group orpyrazinyl group, and R⁸ and R⁹ may bond together with the nitrogen atomto which they are attached to form a 5- or 6-membered saturatedheterocycle through a nitrogen or oxygen atom or not, the heterocycleoptionally containing a substituent selected from the group consistingof a lower alkyl group and a lower alkoxycarbonyl group; and A is alower alkylene group), an imidazolyl-substituted lower alkyl group, alower alkoxy-substituted lower alkyl group, a hydroxyl group-substitutedlower alkoxy-lower alkoxy-substituted lower alkyl group or a lowertrialkyl-substituted ammonium-substituted lower alkyl group;R^(d),R^(e), R^(f) and R^(g) are the same or different and are a hydrogenatom, a lower alkenyl group, a lower alkyl group, a halogen atom, alower alkoxy group, a lower alkenyloxy group, a group of the formula:##STR75## (wherein R⁸ and R⁹ are as defined above), animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a pyridylthio-substituted lower alkyl group, aphenylthio-substituted lower alkyl group optionally containing a loweralkoxy group as a substituent on a phenyl ring, abenzimidazolylthio-substituted lower alkyl group, animidazolylthio-substituted lower alkyl group, a lower alkanoyl group, acycloalkylthio-substituted lower alkyl group, a cyano-substituted loweralkyl group or a lower trialkyl-substituted ammonium-substituted loweralkyl group; (i) R^(c) and R^(g) must not be methyl groups when R^(a),R^(b), R^(d), R^(e) and R^(f) are hydrogen atoms, (ii) R^(g) must not bea methyl group when R^(b), R^(c), R^(e) and R^(f) are hydrogen atoms,and R^(a) an acetyl group, (iii) R^(b) must not be an allyl group whenR^(c), R^(d), R^(e), R^(f) and R^(g) are hydrogen atoms, and R^(a) is anacetyl group, (iv) R^(a) must not be an allyl group or an acetyl groupwhen R^(b), R^(d), R^(e), R^(f) and R^(g) are hydrogen atoms, (v) anyone of R^(d), R^(e), R^(f) and R^(g) must not be a hydrogen atom whenR^(b) and R^(c) are hydrogen atoms and any one of R^(d), R^(e), R^(f)and R^(g) is a lower alkenyl group,or a salt thereof.
 2. A fluorenonederivative represented by the formula: ##STR76## wherein R^(1a) is ahydrogen atom, a lower alkenyl group, a lower alkyl group, a halogenatom, a group of the formula: ##STR77## (wherein A, R⁸ and R⁹ are asdefined in claim 1), an imidazolyl-substituted lower alkyl group, alower alkoxy-substituted lower alkyl group or a hydroxylgroup-substituted lower alkoxy-lower alkoxy-substituted lower alkylgroup,R^(2a) is a lower alkoxy group or lower alkenyloxy group, R^(a)and R^(h) are each a hydrogen atom, a lower alkenyl group or an acetylgroup; s is an integer of 1 to 3,or a salt thereof.
 3. A fluorenonederivative represented by the formula: ##STR78## wherein R^(1a) is alower alkoxy group, a lower alkylthio group, a lower alkanyloxy group ora lower trialkyl-substituted ammonium-substituted lower alkylgroup,R^(2a) is a hydrogen atom, a lower alkoxy, a lower alkenyloxy, alower alkenyl group, a lower alkyl group, a halogen atom, a group of theformula: ##STR79## (wherein R⁸, R⁹ and A are as defined in claim 1), animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a pyridylthio-substituted lower alkyl group, aphenylthio-substituted lower alkyl group optionally containing a loweralkoxy group as a substituent on a phenyl ring,benzimidazolylthio-substituted lower alkyl group, animidazolylthio-substituted lower alkyl group, a lower alkanoyl group, acycloalkylthio-substituted lower alkyl group, a cyano-substituted loweralkyl group or a lower trialkyl-substituted ammonium-substituted loweralkyl group, R^(a) and R^(h) are each a hydrogen atom, a lower alkenylgroup or an acetyl group; s is an integer of 1 to 3; provided that,(1) a4-position of a fluorenone skeleton must not be substituted with R^(1a)when R^(a) and R^(h) are hydrogen atoms or acetyl groups, and R^(2a) arehydrogen atom, r is 1 and R^(1a) is a methoxy group,or a salt thereof.4. A fluorenone derivative represented by the formula: ##STR80## whereinr and s indicate 1 or 2; 1- and/or 3-positions of a fluorenone skeletonare substituted with R^(1a) ; 6- and/or 8-positions of the fluorenoneskeleton are substituted with R^(2a) ; when r is 1, R^(1a) has the samemeanings as R^(b) and R^(c) in claim 1, and when r is 2, one R^(1a) is ahydrogen atom, a lower alkenyl group, a lower alkyl group or a halogenatom and the other R^(1a) is a hydrogen atom, a lower alkyl group, agroup of the formula: ##STR81## (wherein A, R⁸ and R⁹ are as defined inclaim 1), a halogen atom, a lower alkenyl group, animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group or a hydroxyl group-substituted lower alkoxy-loweralkoxy-substituted lower alkyl group; when s is 1, R^(2a) has the samemeanings as R^(d), R^(e), R^(f) and R^(g) in claim 1, and when s is 2,one R^(2a) is a hydrogen atom, a lower alkyl group, a lower alkenylgroup or a group of the formula: ##STR82## (wherein A, R⁸ and R⁹ are asdefined in claim 1) and the other R^(2a) is a halogen atom, a group ofthe formula: ##STR83## (wherein A, R⁸ and R⁹ are as defined in claim 1),a lower alkenyl group, a lower alkyl group, an imidazolyl-substitutedlower alkyl group, a lower alkoxy-substituted lower alkyl group, apyridylthio-substituted lower alkyl group, a phenylthio-substitutedalkyl group optionally containing a lower alkoxy group as a substituenton a phenyl ring, benzimidazolylthio-substituted lower alkyl group, animidazolylthio-substituted lower alkyl group, a lower alkanoyl group, acycloalkylthio-substituted lower alkyl group, a cyano-substituted loweralkyl group or a lower trialkyl-substituted ammonium-substituted loweralkyl group,R^(a) and R^(h) are each a hydrogen atom, a lower alkenylgroup or an acetyl group; s is an integer of 1 to 3; provided that,(1)any one of R^(a) and R^(h) is an acetyl group when R_(1a) and R^(2a) arehydrogen atoms,or a salt thereof.
 5. The fluorenone derivative accordingto claim 1, wherein R^(b) and R^(c) are a hydrogen atom, a lower alkenylgroup or a lower alkyl group, or a salt thereof.
 6. The fluorenonederivative according to claim 5, wherein R^(b) and R^(c) are a halogenatom, a lower alkoxy group, a lower alkylthio group, a lower alkenyloxygroup, a group of the formula: ##STR84## wherein R⁸ and R⁹ are the sameor different and are a hydrogen atom, a lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a pyrimidinyl group orpyrazinyl group, and R⁸ and R⁹ may bond together with the nitrogen atomto which they are attached to form a 5- or 6-membered saturatedheterocycle through a nitrogen or oxygen atom or not, the heterocycleoptionally containing a substituent selected from the group consistingof a lower alkyl group and a lower alkoxycarbonyl group; and A is alower alkylene group, an imidazolyl-substituted lower alkyl group, alower alkoxy-substituted lower alkyl group, a hydroxyl group-substitutedlower alkoxy-lower alkoxy-substituted lower alkyl group or a lowertrialkyl-substituted ammonium-substituted lower alkyl group, animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a hydroxyl group-substituted alkoxy-loweralkoxy-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group, or a salt thereof.
 7. Thefluorenone derivative according to claim 5, wherein R^(d), R^(e), R^(f)and R^(g) are a hydrogen atom, a lower alkoxy group, a lower alkylgroup, a lower alkenyl group, a lower alkenyloxy group or a halogenatom, or a salt thereof.
 8. The fluorenone derivative according to claim5, wherein R^(d), R^(e), R^(f) and R^(g) are a group of the formula:##STR85## wherein R⁸ and R⁹ are the same or different and are a hydrogenatom, a lower alkyl group, a lower alkoxycarbonyl-substituted loweralkyl group, a pyrimidinyl group or pyrazinyl group, and R⁸ and R⁹ maybond together with the nitrogen atom to which they are attached to forma 5- or 6-membered saturated heterocycle through a nitrogen or oxygenatom or not, the heterocycle optionally containing a substituentselected from the group consisting of a lower alkyl group and a loweralkoxycarbonyl group; and A is a lower alkylene group, animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a hydroxyl group-substituted lower alkoxy-loweralkoxy-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group, an imidazolyl-substituted loweralkyl group, a lower alkoxy-substituted lower alkyl group, apyridylthio-substituted lower alkyl group, a phenylthio-substitutedlower alkyl group optionally containing a lower alkoxy group as asubstituent on a phenyl ring, a benzimidazolylthio-substituted loweralkyl group, an imidazolylthio-substituted lower alkyl group, a loweralkanoyl group, a cycloalkylthio-substituted lower alkyl group, acyano-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group, or a salt thereof.
 9. Thefluorenone derivative according to claim 6, wherein R^(d), R^(e), R^(f)and R^(g) are a hydrogen atom, a lower alkoxy group, a lower alkylgroup, a lower alkenyl group, a lower alkenyloxy group or a halogenatom, or a salt thereof.
 10. The fluorenone derivative according toclaim 6, wherein R^(d), R^(e), R^(f) and R^(g) are a group of theformula: ##STR86## wherein R⁸ and R⁹ are the same or different and are ahydrogen atom, a lower alkyl group, a lower alkoxycarbonyl-substitutedlower alkyl group, a pyrimidinyl group or pyrazinyl group, and R⁸ and R⁹may bond together with the nitrogen atom to which they are attached toform a 5- or 6-membered saturated heterocycle through a nitrogen oroxygen atom or not, the heterocycle optionally containing a substituentselected from the group consisting of a lower alkyl group and a loweralkoxycarbonyl group; and A is a lower alkylene group, animidazolyl-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a hydroxyl group-substituted lower alkoxy-loweralkoxy-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group, an imidazolyl-substituted loweralkyl group, a lower alkoxy-substituted lower alkyl group, apyridylthio-substituted lower alkyl group, a phenylthio-substitutedlower alkyl group optionally containing a lower alkoxy group as asubstituent on a phenyl ring, a benzimidazolylthio-substituted loweralkyl group, an imidazolylthio-substituted lower alkyl group, a loweralkanoyl group, a cycloalkylthio-substituted lower alkyl group, acyano-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group, or a salt thereof.
 11. Thefluorenone derivative according to claim 1, wherein R^(a) is a loweralkenyl group, or a salt thereof.
 12. The fluorenone derivativeaccording to claim 4, wherein r and s are 1 or 2; 1- and/or 3 positionsof a fluorenone skeleton are substituted with R^(1a) ; 6- and/or 8positions of a fluorenone skeleton are substituted with R^(2a) ; R^(1a)and R^(2a) are a hydrogen atom, a lower alkyl group or a lower alkenylgroup, or a salt thereof.
 13. The fluorenone derivative according toclaims any one of claims 2 to 4 wherein R^(a) and R^(h) are a hydrogenatom or an acetyl group, or a salt thereof.
 14. The fluorenonederivative according to claims 2, 3 or 4, wherein R^(a) and R^(h) are alower alkenyl group, or a salt thereof. 15.1,3,6,8-Tetrapropyl-2,5-dihydroxyfluorenone. 16.1,3,6,8-Tetrapropyl-2,5-diacetyloxyfluorenone. 17.1,6-Diallyl-2,5-dihydroxyfluorenone. 18.1,4-Diallyl-2,5-dihydroxyfluorenone.
 19. The fluorenone derivativeaccording to claim 1, wherein R^(a) is an acetyl group, or a saltthereof.
 20. The fluorenone derivative according to claim 2, 3 or 4wherein R^(a) and R^(h) are an acetyl group, or a salt thereof.
 21. Thefluorenone derivative according to claim 2, 3 or 4, wherein R^(a) andR^(h) are a hydrogen atom, or a salt.
 22. A method for repairing orprotecting central or peripheral nerve degeneration, which comprisesusing a fluorenone derivative represented by the formula: ##STR87##wherein R¹ is a hydrogen atom, a hydroxyl group, a lower alkenyl group,a lower alkyl group, a halogen atom, a lower alkoxy group, a loweralkylthio group, a lower alkanoyloxy group, a lower alkenyloxy group, agroup of the formula: ##STR88## (wherein R⁸ and R⁹ are the same ordifferent and are a hydrogen atom, a lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a pyrimidinyl group orpyrazinyl group, and R⁸ and R⁹ may bond together with the nitrogen atomto which they are attached to form a 5- or 6-membered saturatedheterocycle through a nitrogen or oxygen atom or not, the heterocycleoptionally containing a substituent selected from the group consistingof a lower alkyl group and a lower alkoxycarbonyl group; and A is alower alkylene group, an imidazolyl-substituted lower alkyl group, alower alkoxy-substituted lower alkyl group, a hydroxyl group-substitutedlower alkoxy-lower alkoxy-substituted lower alkyl group or a lowertrialkyl-substituted ammonium-substituted lower alkyl group;R² is ahydrogen atom, a hydroxyl group, a lower alkenyl group, a lower alkylgroup, a halogen atom, a lower alkoxy group, a lower alkanoyloxy group,a lower alkenyloxy group, a group of the formula: ##STR89## wherein R⁸and R⁹ are as defined above, an imidazolyl-substituted lower alkylgroup, a lower alkoxy-substituted lower alkyl group, apyridylthio-substituted lower alkyl group, a phenylthio-substitutedlower alkyl group optionally containing a lower alkoxy group as asubstituent on a phenyl ring, a benzimidazolylthio-substituted loweralkyl group, an imidazolylthio-substituted lower alkyl group, a loweralkanoyl group, a cycloalkylthio-substituted lower alkyl group, acyano-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group; p and q are an integer of 1 to4; provided that R¹ and R² may be the same or different or a saltthereof.
 23. A method for repairing or protecting central or peripheralnerve degeneration according to claim 22 comprising using the compoundof claim 1 as an active component.
 24. A method for repairing orprotecting central or peripheral nerve degeneration according to claim22 comprising using the compound of claim 2 as an active component. 25.A method for repairing or protecting central or peripheral nervedegeneration according to claim 22 comprising using the compound ofclaim 3 as an active component.
 26. A method for repairing or protectingcentral or peripheral nerve degeneration according to claim 22comprising using 1,3,6,8-Tetrapropyl-2,5-dihydroxyfluorenone as anactive component.
 27. A method for repairing or protecting central orperipheral nerve degeneration according to claim 22 comprising using1,3,6,8-Tetrapropyl-2,5-diacetyloxyfluorenone as an active component.28. A method for repairing or protecting central or peripheral nervedegeneration according to claim 22 comprising using1,6-Diallyl-2,5-dihydroxyfluorenone as an active component.
 29. A methodfor repairing or protecting central or peripheral nerve degenerationaccording to claim 22 comprising using1,4,Diallyl-2,5-dihydroxyfluorenone as an active component.
 30. A methodaccording to claim 22, wherein the fluorenone derivative is representedby formula (A) ##STR90## wherein R^(a) is a lower alkenyl group or anacetyl group; R^(b) and R^(c) are the same or different and are ahydrogen atom, a lower alkenyl group, a lower alkyl group, a halogenatom, a lower alkoxy group, a lower alkylthio group, a lower alkenyloxygroup, a group of the formula: ##STR91## (wherein R⁸ and R⁹ are the sameor different and are a hydrogen atom, a lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a pyrimidinyl group orpyrazinyl group, and R⁸ and R⁹ may bond together with the nitrogen atomto which they are attached to form a 5- or 6-membered saturatedheterocycle through a nitrogen or oxygen atom or not, the heterocycleoptionally containing a substituent selected from the group consistingof a lower alkyl group and a lower alkoxycarbonyl group; and A is alower alkylene group), an imidazolyl-substituted lower alkyl group, alower alkoxy-substituted lower alkyl group, a hydroxyl group-substitutedlower alkoxy-lower alkoxy-substituted lower alkyl group or a lowertrialkyl-substituted ammonium-substituted lower alkyl group;R^(d),R^(e), R^(f) and R^(g) are the same or different and are a hydrogenatom, a lower alkenyl group, a lower alkyl group, a halogen atom, alower alkoxy group, a lower alkenyloxy group, a group of the formula:##STR92## (wherein R⁸ and R⁹ are as above), an imidazolyl-substitutedlower alkyl group, a lower alkoxy-substituted lower alkyl group, apyridylthio-substituted lower alkyl group, a phenylthio-substitutedlower alkyl group optionally containing a lower alkoxy group as asubstituent on a phenyl ring, a benzimidazolylthio-substituted loweralkyl group, an imidazolylthio-substituted lower alkyl group, a loweralkanoyl group, a cycloalkylthio-substituted lower alkyl group, acyano-substituted lower alkyl group or a lower trialkyl-substitutedammonium-substituted lower alkyl group; (i) R^(c) and R^(g) must not bemethyl groups when R^(a), R^(b), R^(d), R^(e) and R^(f) are hydrogenatoms, (ii) R^(g) must not be a methyl group when R^(b), R^(c), R^(e)and R^(f) are hydrogen atoms, and R^(a) an acetyl group, (iii) R^(b)must not be an allyl group when R^(c), R^(d), R^(e), R^(f) and R^(g) arehydrogen atoms, and R^(a) is an acetyl group, (iv) R^(a) must not be anallyl group or an acetyl group when R^(b), R^(d), R^(e), R^(f) and R^(g)are hydrogen atoms, (v) any one of R^(d), R^(e), R^(f) and R^(g) mustnot be a hydrogen atom when R^(b) and R^(c) are hydrogen atoms and anyone of R^(d), R^(e), R^(f) and R^(g) is a lower alkenyl group,of a saltthereof.
 31. A method according to claim 22, wherein the fluorenonederivative is represented by the formula (C) defined in claim
 2. 32. Amethod according to claim 22, wherein the fluorenone derivative isrepresented by the formula (C) defined in claim
 3. 33. A methodaccording to claim 22, wherein the fluorenone derivative is representedby the formula (C) defined in claim 4.